In 2008, Mattek reached a then career-high singles ranking of No. 38 on November 3, 2008, and a then career-high ranking of No. 24 in doubles. At the Grand Slam tournaments, she didn't qualify for the Australian Open, but reached the second round of the French Open and the second round of the US Open. Her best result was at Wimbledon where she reached the fourth round, claiming her first top-10 win over 2007 Wimbledon runner-up Marion Bartoli. She then lost in the round of 16 to fellow American Serena Williams.