But to do so, they would do well to remember if, and how they raced the 2014 edition.
Astana rider Nibali, who is nursing a broken collarbone from a crash at the Olympics, won his maiden Lombardy crown in Como just outside Milan last year.
But the organizers' decision to alternate the start and finish towns between Bergamo and Como for 2014-2017 means the 'Race of the Falling Leaves', like 2014 when Ireland's Dan Martin triumphed, finishes in Bergamo.
The race's marquee Madonna del Ghisallo climb - a 10.6 km ascent at an average gradient of 5.2 % - now comes just 65km into the 241km race instead of in the final third.
Italy's Vincenzo Nibail. Photo: AFP
Five or six climbs that follow suit, two of which have been included for the first time as organizers look for drama in what is the European cycling season's finale.
The world championships will be held in Doha next week, so for some 'Il Lombardia' - one of cycling's five 'monuments' - is a chance to show, gauge and hone form ahead of their national teams' respective bids to secure the coveted rainbow jersey.
Aru is a former Tour of Spain winner whose sole win this season was a stage at the Criterium du Dauphine.
But the 26-year-old Italian warmed up for a tilt at Nibali's crown by finishing sixth in the Milan-Turin in midweek that finished atop Superga.
Aru was given an extra boost after teammate Miguel Angel Lopez triumphed with a nine-second lead on Canadian Michael Woods. But the Italian faces tough opposition.
Spanish veteran Alejandro Valverde (Movistar) pulled out of Milan-Turin with a "light illness but is expected to be among the challengers after successive runner-up places in 2012 and 2013.
Whether Rodriguez feels the same motivation remains to be seen. Spain's 2012 and 2013 winner has been forced to come out of retirement after his Katusha team insisted he race the autumn classics.
The Giro d'Italia last year. Photo: AFP
Dutchman Wout Poels, the Liege-Bastogne-Liege champion, leads the hopes of British outfit Team Sky amid scrutiny and suspicion following reports the team's former star, Tour de France winner Sir Bradley Wiggins, used medicines to gain an unfair advantage on his rivals.
Sky have claimed just two top-ten finishes at the race in six attempts, including Rigoberto Uran's third place finish in 2012.
Uran on Wednesday finished third, at only 14secs behind Milan-Turin winner Angel Lopez.
All the riders still in the race at the 176 km mark, however, will face the fresh challenges of two new climbs for 2016: the Sant'Antonio Abbandonato, followed by Miragolo San Salvatore.
The Abbandonato, 6.5 km long at a gradient of 8.9 percent but with sections at 15 %, begins after 176.1km of racing. Almost 10 km after the summit, the peloton heads into the unknown again with the 8.7 km ascent of San Salvatore (seven percent).
They both come before the day's final major challenge, the 6.9 km Selvino climb whose summit is 28.3km from the finish.
Just to make sure the Lombardy champion is worth his salt, the Bergamo Alta - a small climb which features cobbles and grades up to 12 per cent - has been placed 4 km from the finish.