The Blues are the only Premier League side left in the competition, but they must overturn a 3-1 aggregate deficit from the first leg at the Stadio San Paolo if they are to carry any sort of British interest into the quarterfinals.
Napoli have shown they are no slouches on their first campaign in the competition, helping to eliminate Manchester City in the group stage.
Here are seven factors that Chelsea must take into account when they host the Italian side at Stamford Bridge on Wednesday.
This may seem an obvious one, as stopping the opposition from scoring is a pretty handy strategy in winning any football match, but it is particularly important for Chelsea in this instance.
As things stand, a 2-0 win for the Blues would be enough to see them through thanks to Juan Mata's goal in Naples three weeks ago. Were they to concede one goal at the Bridge, they would then need to score four times in order to progress without the need for a penalty shootout.
The return from injury of captain John Terry at the weekend could well prove a key factor in stopping Napoli's fearsome attack.
For all of their problems this season, and there have been plenty, Chelsea have an excellent home record in Europe this season.
They won all three of their group games in west London, scoring a total of 10 goals past Bayer Leverkusen, Genk and Valencia without conceding once.
Napoli represent the sternest test in the competition for the Blues this season, and as such the home side will need the Stamford Bridge crowd behind them on such an important night.
The atmosphere may not compare to the vociferous support for Napoli's own 60,000-capacity stadium, but the close proximity of the crowd to the pitch will make them an important factor if they can fully get behind their team.
Chelsea attacker Juan Mata summed it up perfectly in an interview with the club's official website when he said: "From the first minute we have to try to create chances to score. We know they have very good strikers and we have to be careful with them, but we will press from the first minute."
The Blues must look to Arsenal's performance against Milan last week, when a first-half blitz of three goals saw the Gunners come agonisingly to cancelling out the Rossoneri's 4-0 advantage from the first leg of their tie.
Of the seven goals Napoli have conceded in the Champions League this season, six have been scored in the opening 45 minutes. Taking that total to eight from nine would put Chelsea in the driving seat in this tie.
The first-leg defeat in Naples was one of the final nails in the coffin for erstwhile Chelsea manager Andre Villas-Boas. The Portuguese coach was fired two matches later, with assistant Roberto Di Matteo placed in interim charge until the end of the season.
The Italian was managing in English football's third tier three years ago, but now finds himself thrust into the helm for a pivotal Champions League game.
This is a tremendous opportunity for Di Matteo to prove he has the mettle to manage at the highest level just 13 months after fears of relegation led to him getting the sack at West Brom. How he reacts to sudden changes in circumstances during the second leg will prove key to Chelsea's success.
An added advantage for Di Matteo in that regard is that his opposite number, Walter Mazzarri, will be serving the second game of his two-match touchline ban, and will therefore not be able to have quite the same influence on the proceedings.
A big fuss was made an hour or so before the first leg when it transpired that Villas-Boas was starting the game with Frank Lampard, Michael Essien and Ashley Cole all on the bench.
Jose Bosingwa was preferred to Cole at left-back as Villas-Boas sought to nullify the threat of right-back Christian Maggio. The Portuguese defender had to withdraw through injury midway through the first half, and Cole had one of his worst games in a Chelsea shirt for years as Maggio gave him a torrid time.
With Chelsea 3-1 down with 20 minutes remaining, Villas-Boas brought on Lampard and Essien, but the pair were unable to kick-start the visitors. If anything, their presence slowed the tempo down just when Chelsea needed to raise the intensity.
The personnel Di Matteo selects for the second leg will perhaps be the most crucial factor of all.
Di Matteo has taken charge of two matches since Villas-Boas' unceremonious departure after just eight months in the Chelsea job. An FA Cup replay against Birmingham City and a Premier League fixture at home to Stoke City have yielded two wins.
Something that was noteworthy in those two victories was that Daniel Sturridge started on the bench for both of them. The English forward came on in the second half in each match, and as such should be fit and raring to go for this crucial Champions League fixture.
Although Sturridge is yet to score in five European appearances this season, he has been a highly effective performer on the right of Chelsea's three-man attack.
The 22-year-old's pace and eye for goal will be a useful asset as Chelsea attempt to chase down their two-goal deficit.
It is not hard to see the basis for Napoli's success over the past year that has seen them finish third in Serie A last season and subsequently reach the knockout phase of their first Champions League campaign.
The attacking triumvirate of Edinson Cavani, Ezequiel Lavezzi and Marek Hamsik is one of the most fearsome attacking units in European football.
Part of the reason why Napoli can commit to such positive football is that they play with only three at the back.
With Chelsea likely to set up with their preferred three-man attack of Didier Drogba, Juan Mata and Daniel Sturridge, they will hope to catch the Napoli wing-backs out of position and get their attackers three-on-three against the visitors' back line.
In such situations the power of Drogba, the pace of Sturridge and the skill of Mata will give Paolo Cannavaro and co. plenty to worry about.