Public health authorities are broadly promoting a strategy known as pre-exposure prophylaxis (PrEP) for the prevention of human immunodeficiency virus (HIV) transmission in the context of high-risk sexual activity and injection drug use. However, there are several limitations to this strategy that are underrecognized. This article reviews the primary literature supporting the use of PrEP and explores the unintended consequences associated with its use. Current public health messaging indicates that PrEP reduces the risk of HIV transmission during sex by 99 percent; however, this figure is based on modeling rather than study findings, and real-world efficacy may be significantly lower. PrEP has been associated with increased rates of sexually transmitted infections, risk compensation, HIV drug resistance, low adherence, and drug side effects. To make fully informed decisions, medical professionals and patients should be aware of these pitfalls. Additionally, this article explores the bioethical implications of prescribing PrEP from a Catholic perspective. Although not always morally illicit, PrEP is most often prescribed in the context of sexual activity outside of marriage between a biological male and female, placing the prescriber in cooperation with activity deemed to be immoral by the Catholic Church. While all medical professionals seeking the common good should aim to reduce the transmission of HIV, not all means are morally licit. Conscience protection for medical professionals opposed to this strategy has become increasingly relevant. Thoughtful discernment is necessary when considering PrEP. The use of CDC material (figure 1) in this article does not imply endorsement by CDC. The material is in the public domain and available on the CDC website free of charge.