HIV acquisition during pregnancy and postpartum periods remains high despite increased access to and initiation of antiretroviral therapy in sub-Saharan Africa. Moreover, maternal seroconversion during pregnancy and breastfeeding remains a source of significant paediatric HIV infection in the region. In order to curb vertical HIV transmission, HIV acquisition during pregnancy and lactation must significantly decline. Biological and behavioural factors contribute to high HIV incidence, including hormonal changes that alter genital mucosal surfaces, and frequent condomless sex with HIV-infected partners or partners of unknown serostatus. Pregnant and breastfeeding women who are at risk of HIV acquisition during pregnancy and lactation require female controlled interventions such as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition during those particularly vulnerable periods. Before PrEP scale up for pregnant and lactating women, there is an urgent need for operations research to evaluate how best to provide PrEP to pregnant and breastfeeding women in settings of high HIV incidence. This should include how to: (1) integrate PrEP delivery and counselling into antenatal and postnatal care, (2) ensure optimal adherence during at-risk periods, and (3) target PrEP for maximum impact, including reaching pregnant and breastfeeding young women. In light of current knowledge on the safety of PrEP in pregnancy and breastfeeding, next steps are needed to ensure barriers to PrEP effectiveness are addressed.