There has been much interest in the potential role of soy in reducing the risk of chronic diseases. Soy foods are uniquely rich in isoflavones, a fact that has triggered much research including intervention studies. However, there have been few long-term prospective observational studies that include disease itself as an outcome. High intake of soy foods is intrinsic to the Japanese diet, which can be advantageous for conducting such studies in Japan. The present report reviews the findings from Japanese prospective cohort studies on soy intake and the risk of cardiovascular diseases, cancer, type 2 diabetes, osteoporosis, menopausal symptoms, and dementia. The results suggest a beneficial role of soy in several chronic diseases, but they are not without controversy. Discrepancies have been observed in the findings of studies of Japanese or other Asians as compared to those of non Asians. This review discusses the issues to be explored in future studies.