Randomized trials have demonstrated that male circumcision (MC) reduces heterosexual acquisition of HIV, herpes simplex virus type 2, human papillomavirus (HPV), and genital ulcer disease among men, and it reduces HPV, genital ulcer disease, bacterial vaginosis, and trichomoniasis among female partners. The pathophysiology behind these effects is multifactorial, relying on anatomic and cellular changes. MC is cost effective and potentially cost saving in both the United States and Africa. The World Health Organization and Joint United Nations Program on HIV/AIDS proposed reaching 80% MC coverage in HIV endemic countries, but current rates fall far behind targets. Barriers to scale-up include supply-side and demand-side challenges. In the United States, neonatal MC rates are decreasing, but the American Academy of Pediatrics now recognizes the medical benefits of MC and supports insurance coverage. Although MC is a globally valuable tool to prevent HIV and other sexually transmitted infections, it is underutilized. Further research is needed to address barriers to MC uptake.