Milan could get back into the Champions League semi-final for the first time since lifting the trophy in 2007, while for Napoli it is an entirely new experience at this level.
The first leg ended 1-0 to the Rossoneri and the decider is at the Stadio Diego Armando Maradona at 20.00 UK time (19.00 GMT).
You can follow all the build-up and action as it happens from that showdown on the LIVEBLOG.
It is true that Milan are one of the most successful clubs in the history of world football, amassing seven editions of the European Cup/Champions League from 1962 to 2007.
However, they have not reached even the semi-final stage since beating Liverpool in the Athens Final in 2007.
The Diavolo reached the quarter-final before elimination against Barcelona in 2011-12, but were absent from the competition entirely for seven years as they battled problems on and off the field.
As for Napoli, being in the quarter-finals is already a club record in the Champions League and Luciano Spalletti reiterated that they have “nothing to lose” in this tie.
They have flourished in another continental competition, winning the UEFA Cup in 1989 during the Diego Maradona era, beating VfB Stuttgart 5-4 on aggregate over two legs in the Final.
The Partenopei also reached the semi-final of the Cup Winners’ Cup in 1977, capitulating to RSC Anderlecht.
Their most recent progress to the semi-final was in the Europa League, losing 2-1 on aggregate to Ukrainians Dnipro in 2015.