Over the past two decades, the global incidence of sexually transmitted infections (STIs) such as gonorrhea, chlamydia, and syphilis have increased significantly, particularly among cisgender men who have sex with men (MSM) and transgender women (TGW). This rise in STIs has spurred interest in new preventive measures, including doxycycline post-exposure prophylaxis (DoxyPEP). Clinical trials in the United States and France have demonstrated the effectiveness of DoxyPEP in reducing both chlamydia and syphilis incidence among MSM and TGW; although, its efficacy against gonorrhea remains limited, and it was further found to be ineffective among cisgender women in Kenya. Due to the promising results, the CDC and the German STI Society have incorporated DoxyPEP into their guidelines for specific high-risk groups. However, the broader implementation of DoxyPEP presents several challenges and ethical concerns. Key issues involve the potential development of antimicrobial resistance, particularly among common STI pathogens like C. trachomatis, M. genitalium, and N. gonorrhoeae, as well as other bacteria such as S. aureus and K. pneumoniae. Additionally, questions concerning equitable healthcare access, the potential impact on adherence to safer sex practices, and broader public health implications warrant careful consideration. Addressing these challenges necessitates a careful balance between the benefits and risks of DoxyPEP, as well as the implementation of strategies to mitigate negative outcomes while maximizing the impact on public health. Lastly, future research should explore the integration of DoxyPEP with other preventive strategies, such as vaccines, to enhance its effectiveness and reduce the global burden of STIs.