Safin was born in Moscow to Tatar parents, Mubin ("Mikhail") Safin and Rauza Islanova. He speaks Russian, English, and Spanish as well as his native Tatar. His parents are former tennis players and coaches. His younger sister, Dinara, is a former world number one professional tennis player and silver medalist at the 2008 Olympic Games in Beijing.

A succession of injuries hindered Safin's progress throughout his career.  In 2003, he missed the majority of the season due to a wrist injury.  During the 2005 clay-court season, Safin suffered a knee injury, which he played through all the way up to Wimbledon with the help of pain killers and anti-inflammatories. Safin was subsequently defeated in the early rounds of each of the seven tournaments he played between the Australian Open and the French Open, culminating in an early round defeat at the French Open. Safin made a surprise finals appearance at the Wimbledon tune-up tournament in Halle on grass. He lost the final narrowly to the defending champion, Federer. He only played one tournament in the summer hard-court season, in Cincinnati, where he lost in the quarterfinals to Robby Ginepri. He also missed the Tennis Masters Cup.  Injuries continued to bother Safin in 2006. Although Safin made appearances at the 2006 ATP Masters tournaments at Indian Wells, Miami, Monte Carlo, Rome and Hamburg, his ranking plummeted to as low as No. 104. He began to recover in time for the 2006 US Open, in which Safin defeated Argentine David Nalbandian, who was then world No. 4 in a riveting second-round match. Safin then lost in the fourth round to former world No. 2 German Tommy Haas, also in a fifth-set tiebreaker. Positive performances at the Thailand Open, where he was narrowly edged out by No. 7 seed, James Blake, and the Kremlin Cup in Moscow, the first all-Russian final at that event, losing to compatriot, Ukrainian-born Nikolay Davydenko, marked Safin's recovery. Despite the injury, Safin still posted 7 wins against top ten players in 2006, fourth-most on the ATP tour behind just Federer (19), Nadal (10), and Blake (8).

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Injuries continued to bother Safin in 2006.