Benzathine penicillin continues to be the cornerstone of recommended therapy for syphilis. Recent increases in the syphilis rates in the United States and concerns about the adequacy of currently recommended therapy for syphilis in patients with concomitant human immunodeficiency virus infection have stimulated reappraisal of alternatives to currently recommended therapy. Desirable features of antimicrobial agents for syphilotherapy include long serum half-life, good penetration into the central nervous system, and ease of administration. Benzathine penicillin provides prolonged treponemicidal levels of penicillin G in serum but does not reliably produce adequate levels of penicillin in the central nervous system. Tetracycline requires multiple daily dosing, has relatively frequent adverse effects, and has unproven efficacy for central nervous system involvement. Erythromycin, which may be less active than tetracycline for syphilis therapy, has similar shortcomings. Recentevaluations ofceftriaxone for early syphilis therapy are promising; however, the optimal dose and duration of therapy are unknown. No currently recommended therapy for syphilis is clearly optimal for reliable, cost-effective therapy. Careful reappraisal of currently available syphilotherapy and alternatives is needed. © 1989 The University of Chicago.