The initial promise of PSA screening was that a simple, accurate blood test would save lives by detecting tumors at an early enough stage to be cured by aggressive treatment. Unfortunately, some 2 decades into the PSA era, the promise of early detection has been tarnished. In the United States, widespread PSA testing led to a higher incidence of early-stage disease, creating an epidemic of prostate cancer in which the lifetime risk of diagnosis increased from 9% to 16%.1 However, a substantial proportion of these PSA-detected cancers likely never would have been found in the absence of screening.2 Nevertheless, as Shao and colleagues highlight, even the lowest-risk tumors are often treated aggressively. These findings lead to the disconcerting realization that an important legacy of the PSA era might be the overdiagnosis and overtreatment of low-risk cancers. Herein, we address the potential harms from PSA testing and the implications for clinical practice.