Millions of men are candidates for testosterone replacement therapy (TRT), but a major safety concern, the effects of TRT on the prostate, has been poorly understood until recently. In the past few years, a meta-analysis showed that endogenous hormone levels have little relationship to prostate cancer. Another review showed that during TRT, cancer develops with no more frequency than in the overall population. A randomized trial focusing on TRT's tissue effects showed that no treatment-related change was noted in prostate tissue composition, hormone levels, biomarkers, gene expression, or cancer incidence. And in animal models, testosterone alone is at most only a weak prostatic carcinogen. Thus, recent years have seen clarification of the prostate safety issue. Future areas of interest include using TRT in men believed to be cured of prostate cancer and, importantly, developing cancer-specific biomarkers (eg, PCA3 gene) to help diagnose and monitor men receiving TRT. © Springer Science+Business Media, LLC 2008.