PURPOSE OF REVIEW: Doxycycline post-exposure prophylaxis (doxy PEP) has proven to be highly effective in reducing the incidence of sexually transmitted infections (STIs) among men who have sex with men (MSM) and transgender women. In response, the US Centers for Disease Control and Prevention (CDC) issued official clinical guidance on the use of doxy PEP as a preventive intervention in these populations. However, despite strong evidence supporting its use, the potential risks of antimicrobial resistance (AMR) along with its limited accessibility in other key populations, remain significant concerns with doxy PEP. RECENT FINDINGS: Real-world data show strong awareness, interest, and usage of doxy PEP among MSM and transwomen. Early ecological studies have revealed population-level reductions in chlamydia and early syphilis incidence following doxy PEP implementation. Ongoing research continues to explore its efficacy in other populations, as well as its impact on both individual and population-level AMR. Doxy PEP is a well-tolerated and inexpensive intervention that has the potential to substantially reduce bacterial STIs, particularly in priority populations. Its implementation will require careful assessment of equitable uptake, usage patterns, and long-term monitoring of STI incidence and AMR.