Liverpool host big-spending Russian outfit Anzhi Makhachkala at Anfield in their Europa League Group A clash on Thursday with the English Premier league side seeking to avoid making unwanted history.
A 3-2 defeat to Udinese in Merseyside on matchday two leaves Brendan Rodgers' men staring at the possibility of consecutive home defeats in Europe for the first time in the club's existence.
Anzhi, thanks to the financial backing from wealthy owner Suleyman Kerimov, have started to flex their muscles this season with Guus Hiddink guiding the Dagestan-based club to the top of the Russian Premier League.
Undefeated in eight European fixtures this season, they will pose a serious threat to a Liverpool side that only secured their first home league win of the campaign on Saturday.
Raheem Sterling's first-half strike proved the difference in a 1-0 victory over struggling Reading, a goal that cemented his status as the club's second-youngest scorer behind Michael Owen and drew praise from his manager.
"The biggest thing for me is maintaining the hunger he's got now because he can be a really top player. It's a long way to go for him but at the moment he's been a revelation," said Rodgers.
"I don't have any concerns about him at this moment. For him, right up until now, he's been brilliant."
Udinese, who ended Liverpool's 13-game unbeaten home run on the continental stage, travel to Switzerland to face Group A doormats Young Boys.
Like his Liverpool counterpart, Newcastle manager Alan Pardew has also used the tournament as a chance to blood some of his less experienced players.
Northern Ireland defender Shane Ferguson received plaudits for an impressive display in the Magpies 3-0 defeat of Bordeaux last time out, and the 21-year-old lauded Pardew's handling of the younger members of the squad.
"The manager has been really good to me this season, giving me a lot of chances, and hopefully I'm taking them.
"(Pardew) has told the youngsters that there are a lot of games and if we work hard we'll have a chance to shine," said Ferguson.
The Group D leaders welcome Club Brugge to St James' Park on Thursday and will aim to maintain their flawless record again Belgian opposition, having won on all six previous occasions.
Bordeaux meanwhile will hope to fare better on their travels as they make the trip to Portugal to face Maritimo.
Unlike predecessor Harry Redknapp whose disdain for the Europa League was well documented, Tottenham boss Andre Villas-Boas has set winning the trophy he won two years ago at Porto as one of the north Londoners' ambitions for this season.
Spurs are looking for their first win after draws against Lazio and Panathinaikos and go to Maribor on the back of a painful 4-2 home defeat to league leaders Chelsea.
Defender Steven Caulker admitted Saturday's result was a bitter pill to swallow but was confident of a positive response in Slovenia.
"The lads are down but we have three away games now with two cup games either side of Southampton, so we'll look to bounce back quickly," said the England under-21 international.
Table-topping Lazio play bottom side Panathinaikos in Group J's other fixture.
Defending champions Atletico Madrid, Lyon and Dnipro enter the third round of fixtures as the only sides with maximum points thus far.
Diego Simeone's Atletico extended their European winning streak to an unprecedented 15 matches with a 1-0 victory over Viktoria Plzen last time out. Next up for Los Rojiblancos is a home tie against Academica de Coimbra from neighbouring Portugal, a side that haven't won a European match since 1969.
Lyon, who failed to qualify for the Champions League for the first time in 13 years, face last season's finalists Athletic Bilbao at Stade Gerland, while French Ligue 1 rivals Marseille are in action at Borussia Moenchengladbach.
Group F leaders Dnipro host Serie A high-flyers Napoli in Ukraine, and Inter Milan are at home to Partizan Belgrade of Serbia.