The global HIV epidemic cannot be controlled by current treatment or prevention strategies. Pre-exposure prophylaxis (PrEP) using antiretrovirals is a promising approach to curbing the spread of HIV transmission. Recently, four clinical trials demonstrated favorable results when antiretroviral PrEP was administered topically or orally. However, two additional trials were unable to demonstrate a benefit, indicating that further study is required to define the populations and conditions under which PrEP will be effective. Adherence is highly correlated with protection, yet the exact level of adherence required is unknown. Future studies may require increased drug exposure testing and more objective methods to monitor adherence in real-time. Although the development of drug resistance in the PrEP trials has been low, it remains a concern, as therapeutic options could be compromised for those who seroconvert while on PrEP.