The Spanish champions, whose chances of retaining their domestic crown faded after a weekend home defeat by Deportivo Coruna, host former European champions Steaua Bucharest in one of 16 first-leg ties in the last 32 on Wednesday and Thursday.
Under pressure coach Claudio Ranieri was given a vote of confidence by Valencia president Juan Bautista Soler on Monday saying the Italian's future at the club would not be discussed until the end of the season.
Valencia, installed as favourites to become the first side to win back-to-back UEFA Cups since Real Madrid in 1986, enter the competition as one of the eight third-placed teams to drop down from the Champions League.
Valencia have gone five league games without a win and will be without suspended Miguel Angel Angulo, who starts a seven-match ban for his sending off in a Champions League match in December. Midfielders David Albelda and Francsico Rufete are doubts after missing training on Monday with thigh strains.
After the bread and butter of the group stage, the return to the knockout rounds has produced a host of intriguing ties.
Nicolas Anelka is no stranger to scoring important goals in European matches and Fenerbahce will expect their new big-money recruit to fire them past Real Zaragoza, who along with Valencia, Sevilla, Villarreal and Athletic Bilbao represent a five-strong Spanish challenge for silverware.
The much-travelled French striker, who scored in both legs for Real Madrid in the semi-final of the 2000 Champions League, bagged his first goal for the Turkish league leaders at the weekend since his move from Manchester City last month.
RUSTY DONETSK
Schalke 04, the 1997 winners, will need to replicate their fine Bundesliga form to gain a first-leg advantage away at Shakhtar Donetsk, who beat Barcelona and Celtic at home in the Champions League group stage.
Donetsk have been active in the transfer market by signing Paraguayan international defender Pedro Juan Benites and four Brazilians this year, the latest being under-20
Donetsk could prove ring rusty with Ukraine's league season still in its winter break while Schalke, second in the Bundesliga and level on points with leaders Bayern Munich, have been boosted by Germany striker Gerald Asamoah's quick return from an injury sustained on international duty.
Italy's sole survivors Parma, twice winners in the 1990s, are embroiled in a fight to avoid relegation from Serie A, and may view the tie with VfB Stuttgart an unwanted distraction.
Four-times European champions Ajax Amsterdam host French club AJ Auxerre in the first leg while in another stand-out tie Sporting Lisbon, whose Alvalade stadium will host the final on May 18, take on Ruud Gullit's free-scoring Feyenoord.
The Rotterdamers warmed up by hitting seven goals for the second week running in the Dutch league at the weekend.
SURPRISING QUALIFIERS
CSKA Moscow's home leg with Benfica will be played in the southern Russian city of Krasnodar, near the Black Sea coast. CSKA were given permission to switch because Moscow's weather in February is too cold to guarantee a decent playing surface.
German second division side Alemania Aachen, who play their UEFA home matches in nearby Cologne, surprisingly qualified from the group stage and take on Dutch title challengers AZ Alkmaar.
Aachen striker Erik Meijer says being a small club has helped their progress in the competition.
"Perhaps our main advantage is that no one has ever heard of us and therefore take us lightly.
"But it hasn't all been luck, we have played some great attacking football as well," Meijer, who had a spell with Liverpool in 1999, told the Observer newspaper.
Last season's semi-finalists Villarreal and Newcastle United travel for first leg matches. Spaniards Villarreal take on Dynamo Kiev while Newcastle go to Dutch side Heerenveen.