Testosterone is a potent hormone with a variety of physiological effects. The diagnosis of androgen deficiency has increased dramatically over the past decade, along with the widespread use of testosterone supplementation therapy (TST). The long-term effects of TST are uncertain, and the risk of overdiagnosis and overtreatment of men who have a normal age-related decline in testosterone is substantial. The biology of the androgen receptor (AR) pathway is complex, and the saturation model does not take the heterogeneity of human prostate cancer into account. Large-scale trials to confirm the safety of testosterone with respect to the risks of prostate cancer and cardiovascular disease with reasonable confidence limits have not been done, and existing data are insufficient to exclude these adverse events. Instead, evidence suggests that prostate cancer could, in fact, be stimulated by TST, and that the risk of cardiovascular events is increased. Overall, TST seems to impose significant risks, and should be used with caution.