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Men who inherit pathogenic germline mutations in BRCA2 and BRCA1 are at increased risk of developing aggressive prostate cancer, and those with germline mutations in other DNA repair genes such as ATM, CHEK2, and MSH2/MSH6 may also have increased risks. Although clinically important, there is lack of specific guidance regarding management strategies for men at increased risk owing to germline mutation status or family history of aggressive prostate cancer. We review prostate cancer genetic risk factors and the ongoing IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) screening study. Pending results of IMPACT and unified guidelines, there are areas of uncertainty and need for further study. Ongoing and future research will be critical for optimizing prostate cancer screening approaches for men at the highest risk for aggressive prostate cancer. In the interim, we propose a practical approach to prostate cancer screening for men with a germline mutation in a known/suspected moderate to high-penetrance cancer predisposition gene (eg, BRCA1/2), and/or men with a first- or second-degree relative with metastatic prostate cancer (regardless of genetic testing): baseline prostate-specific antigen and digital rectal exam by experienced providers at age 40 years or 5 years earlier than age of diagnosis of the youngest first- or second-degree relative with metastatic prostate cancer, whichever is earlier. Then, based on age, digital rectal exam, and prostate-specific antigen, we suggest consideration of magnetic resonance imaging, biopsy, and/or continued monitoring.