Purpose of Review: Seven years after TDF/FTC was approved for pre-exposure prophylaxis to reduce risks of HIV infection, there have been large increases in the number of persons using PrEP in the USA. However, recent data on pre-exposure prophylaxis (PrEP) use at the state level indicate that people living in the Southern United States are underserved by PrEP relative to their epidemic need. We sought to review possible reasons for inequitable uptake of PrEP in the South and identify implementation approaches to increase PrEP uptake in the South. Recent Findings: Published literature, data on the locations of PrEP service providers, recent data on PrEP utilization from pharmacy prescription databases, HIV surveillance data and government data on healthcare providers, and health literacy indicate a confluence of factors in the South that are likely limiting PrEP uptake. A variety of approaches are needed to address the complex challenges to PrEP implementation in the South. These include considering alternative PrEP provision strategies (e.g., pharmacy-based PrEP, telemedicine-delivered PrEP), conducting gain-based stigma-reduction campaigns, increasing capacity for reimbursement for PrEP medications and services through policy change to expand Medicaid and to preserve access to Affordable Care Act–compliant health plans, expanding STI screening programs and improving integration of PrEP offering with delivery of positive STI results, using mHealth tools to screen groups at highest risk for HIV (e.g., men who have sex with men) periodically to increase correct perception of risk, and streamlining clinical procedures to allow same-day PrEP starts for patients without obvious medical contraindications. Summary: Overcoming the structural, capacity, and policy challenges to increasing PrEP uptake in the South will require innovations in clinical approaches, leveraging technologies, and policy changes. The South has unique challenges to achieving equitable PrEP uptake, and addressing key barriers to expanded PrEP use will require multisectoral responses.