Creatine supplementation is an established ergogenic aid in sports and is now claimed to have therapeutical applications in a variety of diseases. The available literature mainly covers the short-term (one to several weeks) effects of creatine supplementation on skeletal muscle function in health and disease, which is of little help to evaluate the long-term (two or more months) potential of creatine as a drug in chronic disorders, such as neurodegenerative diseases or muscular dystrophies. Recent findings in healthy humans indicate that the beneficial effect on muscle function and muscle total creatine content may disappear when creatine is continuously ingested for more than two or three months. The mechanism for this habituation to chronic creatine exposure is poorly understood. The primary purpose of the present review article is to critically evaluate the available evidence for long-term efficacy of creatine administration and to hypothesize about ways to optimize creatine administration regimens.