Given the relatively small impact of prostate cancer screening on cancer mortality, experts are now suggesting that chemoprevention with 5-alpha-reductase inhibitors (5-ARI) may be a more effective strategy for cancer control. Two large placebo-controlled randomized trials found that men receiving 5-ARI were about 25% less likely than controls to be detected with cancer. However, most cancers were detected on routine biopsies required by study protocols. The benefit from receiving 5-ARI was minimal among men who underwent biopsy for clinical indications. Additionally, men receiving 5-ARI were more likely than controls to be diagnosed with high-grade cancers, though post-hoc analyses adjusting for biases accounted for the excess risk in one of the studies. A recent guideline recommended that men considering prostate cancer screening also consider chemoprevention. The rationale is that reducing cancer incidence, given the known risks for overdiagnosis and subsequent overtreatment, is sufficient justification for chemoprevention. However, a large randomized controlled trial found that screening was associated with a 70% increase in prostate cancer diagnosis--which chemoprevention would then reduce by 25%. This does not seem an acceptable trade-off especially because the potential increased risk for high-grade cancers could lead to higher cancer mortality.