There is no easy draw this time. Real Madrid met Roma, Wolfsburg and Manchester City en route to the Champions League final last season, but Los Blancos face a tougher test in the quarter-finals this season and, like Barcelona, will have to do it the hard way in 2016-17.
Madrid were paired with Bayern Munich in Friday's draw in Nyon, while Barca are to face Juventus in the quarter-finals of Europe's premier club competition, meaning the four biggest clubs left in the competition will play one another in the last eight.
It should be exciting and also intriguing. Madrid and Bayern have plenty of history in Europe, with five wins apiece in their 10 ties. Real came out on top in the last of those, a 5-0 aggregate victory in the semi-finals of their Decima-winning campaign of 2013-14.
Carlo Ancelotti was coach back then and Zinedine Zidane his assistant. But now the Italian is Bayern boss and the Frenchman in charge at Real. The master meets the pupil and for Madrid, it is as tough a draw as they could have imagined.
After something of a slow start at Bayern, Ancelotti's side have looked impressive over the past couple of months and the Germans' 10-2 aggregate win over Arsenal in the last 16 highlighted how dangerous they can be in attack.
Madrid, meanwhile, have been shipping too many goals and although Los Blancos advanced comprehensively against Napoli in the end with back-to-back 3-1 wins, there were some uncomfortable moments for the Spanish side at 1-0 down in the second match at the San Paolo.
"It will be a great tie," Bayern midfielder Xabi Alonso said after learning he will be facing his former club in the last eight. "These are two historic teams in Europe and, for me, it will be very special."
Bayern CEO Karl-Heinz Rummenigge added: "They have won the competition 11 times. Our motivation is great. But there's a law that states that the defending champion does not retain the trophy, so that's in our favour."
Indeed, no side has been able to claim the title back to back in the Champions League era and Madrid, winners in two of the past three seasons, will look to break that statistic - although they will have to beat Bayern first.
Barcelona also face a difficult route to the last four with their tie against Juventus - a repeat of the 2014-15 final in Berlin when Luis Enrique's side won the trophy to complete the treble.
Juventus are perhaps the most consistent team in Europe this term and Pavel Nedved said: "The challenge comes at the right time. We are aware of our strength and we respect Barcelona, but we won't fear them."
The tie sees Dani Alves meet the club where he spent eight successful seasons and Nedved said: "[Leonardo] Bonucci and [Paulo] Dybala wanted Barca, but Dani Alves wanted to avoid them."
Most Juve fans probably wanted to avoid Barca, too, while Madrid supporters will be wary of both Bayern and Ancelotti. So, while they remain favourites in the Champions League, the two Clasico rivals will have to do it the hard way to advance to the last four this time.