Williams booked her place in the last four by ending Petra Kvitova's reign as champion with a 6-3, 7-5 victory on Tuesday, while Azarenka moved into her second successive Wimbledon semi-final by defeating unseeded Austrian Tamira Paszek 6-3, 7-6 (7/4).
That sets the stage for a fascinating clash between one of Wimbledon's all-time greats and a talented contender in Azarenka who has already enjoyed the best year of her life after winning a series of titles including her first Grand Slam crown at the Australian Open.
Williams, who last won a Grand Slam at Wimbledon in 2010, has been impressed by Azarenka's rise over the last six months, but the American believes the lack of pressure she feels at the moment could be the decisive factor as it allows her to go for broke at crucial moments.
"She's playing unbelievable and already having a Grand Slam under her belt is really great. She did it in such style, so it's not going to be easy if I play her," Williams said.
"It's going to be another match where I have absolutely nothing to lose. I can just go out there and enjoy myself and have fun.
"Right now if Victoria beats me, she's had a better year than I have.
"Going against a player like that, I feel like she almost has an advantage. So that makes me really relaxed and I can just kind of hit."
For Azarenka, the 22-year-old's meeting with 13-time Grand Slam champion Williams represents a chance to make amends for last year's Wimbledon semi-final defeat against Kvitova, and also a quarter-final loss to Williams in 2009.
"It's a great feeling to be in a semi-final of a Grand Slam but I still want to go all the way and it seems still far away," Azarenka said.
"There's no better opponent than Serena, I'm really looking forward to it. It's not going to be easy but it's the semi-final of a Grand Slam - what else do you expect?"
The other semi-final between eighth seed Angelique Kerber and world number three Agnieszka Radwanska will produce a first-time Wimbledon finalist.
Kerber defeated fellow German Sabine Lisicki 6-3, 6-7 (7/9), 7-5 to reach her first Wimbledon semi-final.
Just 12 months ago, the 24-year-old left the All England Club ranked 100th after a first round exit that came during a miserable sequence of opening round defeats.
But a period of reflection after Wimbledon refocused Kerber's mind and she has surged up the rankings to eighth place since a breakthrough run to the US Open semi-finals last year.
"After I lost at Wimbledon last year I decided to take a break and had three weeks practice before I went to New York. I think this was the tournament that changed everything for me," Kerber said.
"My goal was just to play one round there and win one round. I did that, then suddenly I felt I was in the tournament. After that I really started to believe in myself."
Kerber, who beat Radwanska during that US Open run, added: "It will be a long match and a tough one against Radwanska because she moves very well on grass. She doesn't make a lot of mistakes.
"It's not been easy when I have played her and I know that I need to play on my high level to beat her, but I have nothing to lose now."
It will also be a defining moment for Radwanska, who ignored a series of rain delays to defeat 17th seed Maria Kirilenko 7-5, 4-6, 7-5 in a match that started on Court One at 2.20pm local time, but was eventually played to a conclusion under the Centre Court roof after 9.45pm.
The 23-year-old is the first Polish player to reach a Grand Slam semi-final in the Open era after finally win in the last eight of a major at the sixth attempt.
"I'm just very, very happy," said Radwanska. "It's the first time I reached the semi-finals and there's no words to describe it."
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