PURPOSE OF REVIEW: This review examines the growing need for alternative technologies to address the resurgence of syphilis, particularly its congenital and late-stage manifestations. It explores current treatment paradigms, highlights the limitations of penicillin, and evaluates emerging evidence on new therapies and diagnostics to inform future strategies. RECENT FINDINGS: Recent breakthroughs in Treponema pallidum culture techniques have enabled antibiotic susceptibility testing, expanding knowledge on both established and emerging treatment options. Alternatives like ceftriaxone, doxycycline, cefixime, and dalbavancin show promise, with other candidates in trials, though evidence is limited beyond early-stage syphilis. Shortened penicillin regimens also challenge historical assumptions about treatment duration. Advanced molecular diagnostics may complement currently limited serologic monitoring to improve evaluations in healthcare and research. While penicillin remains effective, its limitations necessitate alternatives. Emerging antibiotics and improved diagnostics offer opportunities to simplify treatment and enhance care. Future robust trials should validate new treatments, refine dosing strategies, and integrate innovative diagnostics, particularly including underserved and vulnerable populations.