The Russian superstar has collected five Grand Slam titles - including the 2004 Wimbledon crown -and built a global brand that makes her the world's highest paid female athlete.
But the 28-year-old has still been left trailing in Serena's wake and she hasn't come out on top since 2004.
The 33-year-old American has a 17-2 lead in their head to head record, winning their last 16 meetings and depriving Sharapova of three major titles - in the 2007 and 2015 Australian Open finals and the 2013 French Open final.
Serena has also won all four of her semi-final meetings with Sharapova, defeated the Russian in their previous Wimbledon clash in the last 16 in 2010 and routed her in the 2012 Olympic final at the All England Club.
After battling back to defeat Victoria Azarenka in the last eight - extending her winning run at Grand Slams to 26 matches and her 2015 record to 37-1 - Serena can't wait to take on Sharapova again.
"I love playing Maria. I think she brings out the best in me. I thought we had a wonderful final in Australia," said Serena, who remains on course to hold all four major titles at once and is in the hunt to clinch the first calendar Grand Slam since 1988.
"For me, I don't feel like I have any pressure going into this match. It's just totally different for me. I don't have anything to prove. I won all the Grand Slams, multiple times. Now it's just I'm here just to enjoy it."
Sharapova caused one of the great Wimbledon shocks 11 years ago when, aged just 17, she defeated Serena in the final to claim her first Grand Slam title.
The duo's relationship has remained frosty ever since, occasionally turning nasty - as it did when they traded barbs about Sharapova dating Williams' ex-boyfriend Grigor Dimitrov and the American's own relationship with her French coach Patrick Mouratoglou. Sharapova is in her fifth Wimbledon semi-final and her first since 2011.
Asked if her lack of success in the Serena match-up would be weighing on her mind, Sharapova gamely insisted she still relishes the challenge of playing the American.
"I think it's always a new match. I haven't had great success against her. I would love to change that around. That's how I look at it," the world number four said.
The other semi-final may end up being overshadowed by Serena v Maria Part 20, but there is still plenty of intrigue in the meeting between Agnieszka Radwanska and Garbine Muguruza. Radwanska is in her fourth Grand Slam semi-final and her third at Wimbledon.
The Polish 13th seed reached the Wimbledon final in 2012, losing to Serena, and she hopes her experience of the latter stages of a major will stand her in good stead against Spanish 20th seed Muguruza, who will be appearing in the last four of a Grand Slam for the first time.
Muguruza, 21, is the first Spanish woman to make the Wimbledon semi-finals since Arantxa Sanchez-Vicario in 1997.