HIV-serodiscordant couples face complicated choices between fulfilling reproductive desire and risking HIV transmission to their partners and children. Sexual HIV transmission can be dramatically reduced through artificial insemination and sperm washing; however, most couples cannot access these resources. We propose that periconception pre-exposure prophylaxis (PrEP) could offer an important, complementary therapy to harm reduction counseling programs that aim to decrease HIV transmission for couples who choose to conceive. In this paper, we describe the potential benefits of periconception PrEP and define critical points of clarification prior to implementation of PrEP as part of a reproductive health program. We consider sexual transmission risk, current risk reduction options, PrEP efficacy, cost, adherence, resistance, fetal toxicity, and impact of PrEP counseling on entry into health services. We address PrEP in the context of other periconception HIV-prevention strategies, including antiretroviral treatment of the HIV-infected partner. We conclude that, should PrEP prove safe and efficacious in ongoing trials, periconception PrEP may offer a useful approach to minimize risk of HIV transmission for individuals of reproductive age in HIV-endemic countries.