He played for the Waterloo Black Hawks of the United States Hockey League. Collegiately, he played one year at Ferris State University before transferring the University of North Dakota, and starred on their 1996-1997 National Championship team. Blake was signed as a free agent by the Los Angeles Kings in 1999. In January 2001, he was acquired by the New York Islanders in a trade with the Los Angeles Kings, who received a conditional pick in 2002. Blake set career highs in goals and points during the 2005–06 season with 28 and 57, respectively. The following season he topped both totals, scoring 40 goals and 69 points. The 40th goal was scored against the Toronto Maple Leafs on April 5, 2007. Along with Islanders teammates Rick DiPietro and Mark Parrish, Blake was part of Team USA at the Winter Olympics held in TurinItaly in February 2006. Team USA was led by Peter Laviolette, his former coach with the Islanders. Blake scored his 100th career NHL goal against the Chicago Blackhawks at the Nassau Veterans Memorial Coliseum on October 31, 2006. The milestone 100th goal came on the power play late in the 3rd period. Blake was named an all-star for the first time in his career during the 2006–07 NHL season. He recorded 2 assists in the 2007 NHL All-Star Game. At the end of the 2006–07 season Blake became an unrestricted free agent. He was quoted in Newsday in February 2007 saying he would probably test the free agent market if not re-signed by the Islanders prior to the NHL trading deadline. Blake was neither traded nor re-signed before the deadline and on July 1, 2007, Blake signed with the Toronto Maple Leafs to a 5-year contract worth US$20 million. On October 8, 2007, Blake announced that he had been diagnosed with chronic myelogenous leukemia, a rare, but highly treatable form of cancer. He continued to play for the Maple Leafs for the rest of the season. In Blake's first season with Toronto he played in all 82 regular season games. He scored 15 goals and added 37 assists for a total of 52 points. While he managed a considerable number of points, he struggled to score goals all season, having over 300 shots on goal, easily a career high, but only 15 goals. He was awarded the Bill Masterton Trophy at the end of the season for perseverance and dedication to hockey through the difficult times he faced after being diagnosed with cancer. In the 2009–10 season, Blake was traded to the Anaheim Ducks along with Vesa Toskala for Jean-Sébastien Giguère on January 31, 2010.