Mattek-Sands then suffered a major knee injury in 2017 that required surgery and a year away from competition to heal, but eventually came back to win the 2018 and 2019 US Open mixed doubles titles, both partnering Jamie Murray.

Her best results in singles on the WTA Tour are reaching the fourth round of two major events (Wimbledon in 2008 and the French Open in 2013), the semifinals of the tournaments in Cincinnati in 2005 and Birmingham in 2008, and the final of the Bell Challenge in 2008 and 2010.

Then in 2000, she received a wildcard into qualifying at the International Players Championships in Key Biscayne but lost in the first round to Anca Barna.

She played her first main draw as a wildcard at a Grand Slam tournament in the US Open but lost to Australia's Alicia Molik in the first round.

In November, she reached her first ever WTA tournament final at the Bell Challenge in Canada, before losing to the top seeded Nadia Petrova.

Her good form continued into the Hobart International, where she reached her third career WTA singles final, before losing to Jarmila Groth.

Her next event was a Fed Cup tie against Belgium in Antwerp, where she lost to Yanina Wickmayer in the opening rubber, and later to Kim Clijsters.

Pairing with Shaughnessy, the American duo made it to the doubles finals losing to Sania Mirza and Elena Vesnina.

Mattek-Sands next entered a small clay event in Estoril where she was the fifth-seeded player in singles, but was then upset in the first round by Monica Niculescu.

Mattek-Sands played in the French Open and made it to the third round, which was her best result at this major in her career thus far, before losing to the higher-seeded as well as her good friend, Jelena Janković.

After an early exit from the Hopman Cup, she played singles at the Hobart International, where she was a finalist, and doubles with partner Gajdošová.

In the mixed doubles competition, she and Romanian partner, Horia Tecău finally had their breakthrough moment, defeating title favorites, Bhuphati/Mirza in the semifinals.

However, with Mirza in doubles, she reached the quarterfinals of Montreal and the third round of the US Open, playing eventual champions Sara Errani and Roberta Vinci to three sets.

At home event in Charleston, she brushed aside fellow American and that year's Australian Open semifinalist Sloane Stephens, before losing to Madison Keys in third round.

Both defeated players would go on to reach semifinals of the first Grand Slam event of the season, which made Mattek-Sands' wins bigger.

In September 2016, hacked documents from the World Anti-Doping Agency (WADA) revealed that Mattek-Sands had twice applied for a therapeutic-use exemption for hydrocortisone and DHEA.

Both times the request was granted by the International Tennis Federation before being revoked by WADA, but an application for exemption for hydrocortisone alone was eventually approved.

Their winning streak continued over in Beijing, where Mattek-Sands and Šafářová claimed the title again Caroline Garcia and Kristina Mladenovic.

At the WTA Finals, Mattek-Sands and Šafářová defeated Tímea Babos and Yaroslava Shvedova in the quarterfinals, and their rivals Caroline Garcia and Kristina Mladenovic in the semifinals.

The pair won their second Australian Open doubles title in three years, and their second straight Grand Slam tournament, defeating Andrea Hlaváčková and Peng Shuai in the final, in three sets.

Mattek-Sands won the French Open women's doubles title, again with Šafářová, by beating Ashleigh Barty and Casey Dellacqua, in straight sets.

Playing Sorana Cîrstea in the second round of the Wimbledon singles, Mattek-Sands was running to the net at the beginning of the third set when she collapsed in agony, clutching at her right knee.

She was treated on the court before being rushed to a local hospital with an "acute knee injury" which was later revealed to be a dislocated kneecap and ruptured patellar ligament, for which surgery was required.

The pair, who were playing just their third event together, reached the final[15] in which they were defeated by Czech duo Barbora Krejčíková and Kateřina Siniaková in straight sets.

At the 2023 Italian Open, she reached the semifinals with Marie Bouzková using protected ranking; they lost to fourth seeds and eventual champions, Elise Mertens and Storm Hunter.

[16] In March 2024, partnering Sofia Kenin, she won her second Miami title and seventh overall at the WTA 1000 level, having entered the tournament as alternates.

[17] At the 2024 Prague Open in July, she reached the final with Lucie Šafářová where they lost to top seeds Barbora Krejčíková and Kateřina Siniaková.

[22][23][24] During the 2011 pre-Wimbledon party in London, Mattek-Sands wore a fluorescent green dress, by designer Alex Noble, that featured tennis balls as components and a Mohican-style hat.

Only main-draw results on WTA Tour, Grand Slam tournaments, Fed Cup/Billie Jean King Cup and Olympic Games are included in win–loss records.

The team advanced to the final as the second seed with a win over the Orlando Storm in the semifinals, but ultimately fell in the Championship match to the New York Empire in a Supertiebreaker.