Six major climbs are spread across the 239-kilometre course, including the famous Madonna del Ghisallo, while there's a final sting in the tail in the form of the steep and cobbled Colle Aperto three kilometres from the line.
Five former winners will be among those looking to end their year with another triumph, while a number of other big names will be aiming to taste victory in Lombardia for the first time – including two of this year's Grand Tour winners and the reigning world champion.
With fewer than 24 hours to go until the fifth Monument kicks off, here's a look at 10 of our riders to watch for Il Lombardia.
Well, this is cheating, but the Belgian team have three potential winners among their number on Sunday in the shape of world champion Julian Alaphilippe and the in-form youngsters Remco Evenepoel and João Almeida.
Alaphilippe comes into the race with the number one on his back as team leader and reminded everyone exactly what he's capable of – as if it was needed – with a 17-kilometre solo victory at the World Championships in Leuven two weeks ago. He could do something similar in Bergamo, or win a small sprint, and, ominously for his rivals, said earlier this week that "I feel good and motivated" heading into the final race of his season.
Almeida has shown his top form this week with a second place at the Giro dell'Emilia and third at Milano-Torino, at both races mixing it up with some of the other names on this list. Between the Portuguese rider, Alaphilippe, and Evenepoel – who was fifth at Emilia and won the Coppa Bernocchi with a 30-kilometre solo attack – Deceuninck-QuickStep are the strongest team at the race, and it wouldn't be a surprise to see any of the trio celebrating at the finish.
Primoz Roglic (Jumbo-Visma)
The QuickStep trio will have to get past a very in-form Primož Roglič to do that, though. The Slovenian recorded his 12th and 13th wins of the season at Emilia and Milano-Torino in the past week. At the latter he beat an elite group on the uphill finish of San Luca in Bologna, and at the former he left Adam Yates behind on the Superga.
Of course, Il Lombardia doesn't finish with an uphill finish, so a repeat of those wins isn't on the cards. But Roglič is no slouch in a reduced sprint – he beat two of the men on this list in the flat finish at last year's Liège-Bastogne-Liège, remember – and with the final hill of the day coming three kilometres from the finish, you can't bet against him going solo with his fearsome acceleration, either.
Roglič will look to last year's runner-up, the UAE Team Emirates-bound George Bennett, for support, while Tour de France runner-up Jonas Vingegaard is another option, though both men will be firmly second options behind the 31-year-old on Saturday.
Tadej Pogacar (UAE Team Emirates)
The two-time Tour champion is impossible to ignore even if he hasn't won a race since taking yellow in Paris just over two months ago. Since then, Tadej Pogačar has taken road race bronze at the Tokyo Olympics, finished fifth at the European Championships road race, and registered relatively anonymous rides at the Worlds.
He looks to be heading back to his peak in time for Il Lombardia, though, having taken third place at Tre Valli Varesine on Tuesday and fourth alongside Almeida at Milano-Torino, though on both occasions he was over 30 seconds off the win.
The 23-year-old will be making his debut at the race on Saturday, but he already has a strong Classics pedigree, having beaten Alaphilippe to victory at Liège-Bastogne-Liège back in April and finished third at La Doyenne last year. Pogačar, Alaphilippe and Roglič already have packed palmarès, and each are missing Il Lombardia, so this year's race could bring an almighty battle of the titans.
Dan Martin and Michael Woods (Israel Start-Up Nation)
Dan Martin makes our list as a past winner of Il Lombardia, having triumphed with a late attack seven years ago, and also as a man pinning on his race numbers for the final time.
The 35-year-old may not be among the top, top favourites for Saturday, but – as we saw in May's Giro d'Italia – he still has the ability to fight for victories with the cycling's megastars. He was up at the top of the standings at the Giro dell'Emilia last Saturday, taking sixth place, and will no doubt be seeking to end his 14-year career on the highest note possible with a third Monument victory.
Michael Woods, meanwhile, is often prominent at this time of year, his skills well suited to the steep inclines found at Italy's autumn Classics. In recent seasons he has won and finished second at Milano-Torino, placed second and fourth at the Giro dell'Emilia, and taken fifth at Il Lombardia two years ago.
This time around he's in good form once again, grabbing third at Emilia and fifth in Milano-Torino. The Canadian has a useful sprint on him, but he wouldn't be the favourite if he goes to the line with the likes of Alaphilippe or Roglič. Look, instead, for him to take a flier – perhaps on the steep final climb of the day close to the finish.
Bauke Mollema (Trek-Segafredo)
Bauke Mollema is the second past winner on our list, and he's another who flourishes late in the season, having taken four of his 17 career victories in the hinterlands of October. Two years ago, the Dutchman surprised the other favourites with an attack 18 kilometres from the line to take a famous solo victory.
It'll be hard to do so again on Saturday, not least because he'll be more of a marked man this time. He should be recovered from his heavy crash at last month's Tour de Luxembourg, though. He said at the Worlds that the crash prevented him from being on top form there, but last week he took a creditable seventh place at the Giro dell'Emilia.
Mollema will be co-leader of Trek-Segafredo at Il Lombardia, alongside fellow veteran and past winner Vincenzo Nibali. The Italian, who moves back to Astana Qazaqstan next season, won the Giro di Sicilia at the start of the month, but, at this point in his career, a third victory here would come more in shock than expectation.
Adam Yates (Ineos Grenadiers)
Adam Yates, closing out his first season at Ineos, has enjoyed what is arguably the best season of his career to date in 2021. The Briton's overall title at the Volta a Catalunya was the 16th of his career and certainly the most prestigious, and he salvaged a fourth place for his team at the Vuelta a España, missing a first Grand Tour podium of his career by 1:26 in Madrid.
He was close to adding another win to his palmarès at Milano-Torino, too, racing alongside Roglič up the final climb of the Superga before being unable to match the Slovenian's final attack to the line. Still, he's in very good form, having beaten Almeida, Pogačar and Woods in Turin, and will be among the favourites once again at the weekend.
Yates is backed up by a strong team, too, though – unusually for Ineos – he looks set to be certain sole leader. Pavel Sivakov and Tao Geoghegan Hart aren't on his level of form at the moment, but they and Gianni Moscon will be valuable lieutenants.
David Gaudu (Groupama-FDJ)
Finally, we come to David Gaudu, who has taken his riding to another level this season. At 24, the Frenchman has moved from being the next big thing in the country to being a real contender for some of cycling's biggest prizes.
This season, he has won stages at Itzulia Basque Country and the Tour de Luxembourg, finished third at Liège-Bastogne-Liège, seventh at the Tokyo Olympics road race, and won the white jersey at the Critérium du Dauphiné.
That one big victory is still missing though, and he's coming into form ahead of the race he finished 11th at two years ago having taken top 10 placings at Tre Valli Varesine and Milano-Torino. He may still be a step below some of the other favourites, but he – and teammate Thibaut Pinot – are still ones to watch.
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