Creatine is naturally synthesized in the human body from amino acids primarily in the kidney and liver and transported in the blood for use by muscles. Approximately 95% of the body's total creatine content is located in skeletal muscle.
 
Creatine was discovered in the 1800s as an organic constituent of meat. In the 1970s, Soviet scientists reported that oral creatine supplements may improve athletic performance during brief, intense activities such as sprints. Creatine gained popularity in the 1990s as a "natural" way to enhance athletic performance and build lean body mass. It was reported that skeletal muscle total creatine content increases with oral creatine supplementation, although response is variable. Factors that may account for this variation are carbohydrate intake, physical activity, training status, and muscle fiber type. The finding that carbohydrates enhance muscle creatine uptake increased the market for creatine multi-ingredient sports drinks.
 
Use of creatine is particularly popular among adolescent athletes, who are reported to take doses that are not consistent with scientific evidence, and to frequently exceed recommended loading and maintenance doses.
 
Published reports suggest that approximately 25% of professional baseball players and up to 50% of professional football players consume creatine supplements. According to a survey of high school athletes, creatine use is common among football players, wrestlers, hockey players, gymnasts, and lacrosse players. In 1998, the creatine market in the United States was estimated at $200 million. In 2000, the National Collegiate Athletic Association (NCAA) banned colleges from distributing creatine to their players.

Creatinine excreted in urine is derived from creatine stored in muscle.