Prostate-specific antigen (PSA)-based early detection for prostate cancer is the subject of intense debate. Implementation of organized prostate cancer screening has been challenging, in part because the PSA test is so amenable to opportunistic screening. To the extent that access to cancer screening tests increases in low- and middle-income countries (LMICs), there is an urgent need to thoughtfully evaluate existing and future cancer screening strategies to ensure benefit and control costs. We used Mexico's prostate cancer screening efforts to illustrate the challenges LMICs face. We provide five considerations for policymakers for a smarter approach and implementation of PSA-based screening.