The clubs meet in France on Sunday before the return leg in England on April 28, with a place in the final in Budapest on May 18 up for grabs.
The winner of that tie will take on either Bayern Munich or Barcelona, who go head to head in Germany in the first leg of their last-four clash on Sunday.
Chelsea's reward for ousting Paris Saint-Germain in the last round is another trip to France, but getting the better of an all-conquering Lyon side is likely to be another challenge altogether.
The English side beat PSG 3-2 on aggregate in the quarter-finals thanks to a dramatic injury-time goal by Norwegian midfielder Maren Mjelde, and are through to the last four for the second season running.
Last year their European dream was ended by German club Wolfsburg, who went on to lose to Lyon in the final in Kiev.
Lyon have won the Champions League five times overall and closed on their 13th consecutive French title by hammering rivals PSG 5-0 last weekend before a crowd of 25,907, a record for a women's game in France.
Ballon d'Or winner Ada Hegerberg set Lyon on their way with her 19th league goal of the season. She has also netted four times in the Champions League, but was eclipsed in the quarter-finals by Eugenie Le Sommer, scorer of three goals in Lyon's 6-3 aggregate victory over Wolfsburg.
It all points to a gargantuan task for Chelsea, who are coming off the back of an agonising defeat against Manchester City in the FA Cup semi-finals last weekend and are hoping to keep the tie alive before the return in Kingston upon Thames on April 28.
"Nobody's delusional, Lyon are the best team in Europe, where they should be with a budget four times bigger than anyone else's," Chelsea manager Emma Hayes told the club's website.
"They've got enough trophies under their belt to warrant the position they're in — they're overwhelming favourites, so we are going to have a glorious time."
Two giants of the men's game, these clubs are relative novices at this level of the women's scene, especially Bayern.
Runners-up to Wolfsburg in Germany in the last couple of years, they are second in the table again this season. However, they made it to the last four of the Champions League for the first time after defeating Slavia Prague in the quarters.
Barcelona, meanwhile, made it to this stage in 2017, only to lose to PSG. Now they are targeting a first final.
Engaged in a thrilling battle with Atletico Madrid for the Spanish title, the Catalans are wary of Bayern's threat, however.
"We must not forget that they are a team with a much bigger budget than us and who have the best German players," claimed Barcelona coach Lluis Cortes.
Nevertheless, Barcelona boast an impressive array of attacking talent, from England's Toni Duggan to Dutch star Lieke Martens and Spanish international Alexia Putellas.
Bayern will look to Mandy Islacker for inspiration in attack — she scored twice against Slavia in the last round and got the winner for Frankfurt in the 2015 final.
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