Metabolic syndrome was initially described as an aggregation of risk factors for the development of coronary artery disease with insulin resistance and compensatory hyperinsulinemia as the underlying factor. In an earlier review, we suggested that hyperinsulinemia may also lead to prostate cancer (PCa), the most common male cancer in industrialized nations. Furthermore, we suggested that diet and exercise, known to be important in the development of insulin resistance, may also be important in the development of PCa. When we placed men from the United States on a low-fat diet and/or exercise program, serum levels of insulin, free testosterone, estradiol and insulin-like growth factor (IGF)-1 were reduced while sex hormone-binding globulin (SHBG) and insulin-like growth factor binding protein (IGFBP)-1 were elevated. These in vivo serum changes directly impacted on androgen-dependent prostate cancer cell lines in vitro to reduce cell growth and induce apoptosis. The reduction in serum IGF-1 and increase in IGFBP-1 with diet and exercise appear to be the most significant, as these changes lead to an increase in tumor cell p53 protein and its down-stream effector p21, which are responsible for the reduction in cell growth and induced apoptosis. Preliminary results from a clinical study with men on "watchful waiting" indicate that the observed in vitro effects of diet and exercise on prostate cancer cell growth also occur in vivo.