A global human immunodeficiency virus (HIV) epidemic persists despite data to support multiple effective and safe tools that prevent HIV transmission and acquisition. Human immunodeficiency virus preexposure prophylaxis (PrEP) for HIV-uninfected at-risk populations using tenofovir disoproxil fumarate emtricitabine is highly effective, safe, and recently endorsed by the US Preventive Services Task Force (USPSTF) as a grade A recommendation. In this Special Communication, we summarize current guidelines and expert recommendations in a call for wider adoption of PrEP prescribing activities by frontline primary care clinicians. Key components include the ideal contexts in which PrEP may be prescribed, eligibility criteria, clinical considerations and pitfalls, laboratory monitoring, prescription practices, situations that may warrant expert consultation, and future directions. Given the broad scope, access, and point-of-entry status of primary clinicians in health systems, generalists will need to be at the center of any successful effort to leverage the power of, and destigmatize PrEP to end the HIV epidemic.