Chelsea must overcome a deficit in the second leg if they to progress to the Europa League quarter-finals, while Inter Milan need a miracle.
Inter suffered a 3-0 defeat away to Tottenham Hotspur in their first leg, with in-form star Gareth Bale the chief destroyer again, re-living the memories of his Stadio Giuseppe Meazza hat-trick in 2010.
The Italian side have struggled in Serie A this season, sitting fifth in the table, and it is going to take a huge effort from them to get back in the tie and deny Tottenham an away goal, particularly with Bale in such lethal form.
Chelsea face a smaller hurdle after going down 1-0 at Steaua Bucuresti in their first leg, with the Romanian side taking it right up to last season's surprise Champions League winners.
Interim coach Rafael Benitez will still be confident of progressing, with the second leg at Stamford Bridge, but the west London side must be wary of the Romanian visitors pinching an away goal.
Lazio are in pole position to progress in their tie against Stuttgart, leading 2-0 from the first game in Germany, with the second leg to be played in Rome.
After securing an away goal in a 1-0 win against Napoli's conquerors Viktoria Plzen, Fenerbahce will be favourites to progress in front of their home fans.
A 2-0 victory for Basel against Zenit St. Petersburg in their first leg leaves the Russian side with it all to do in the second leg in Switzerland.
Newcastle will hope home advantage helps secure their passage as they welcome Anzhi Makhachkala to St James' Park after a 0-0 draw in Moscow.
Rubin Kazan are in a similar position as they host Levante after both teams failed to find the net in the opening leg.
Finally, Benfica will attempt to defend a 1-0 aggregate lead as they travel to Bordeaux for their second leg.