The dramatic increase in syphilis cases in the United States in recent years is a serious public health concern. Periodic shortages of benzathine penicillin G (BPG), the mainstay of syphilis treatment, create challenges for management of syphilis in the United States and worldwide. The National Institute of Allergy and Infectious Diseases convened working groups of experts to assess the landscape of syphilis treatments for uncomplicated adult syphilis, syphilis in pregnant women, congenital syphilis, and neurosyphilis. The working groups came together at a workshop entitled “Alternative Therapies to Penicillin for the Treatment of Syphilis” on February 13 to 14, 2024, to share their findings regarding promising alternative treatments, research gaps, and challenges. Discussions focused on using existing antibiotics, with a preference for those with favorable safety profiles and demonstrated success against syphilis or other infectious diseases. Clinical research on alternative treatments is complicated by the high effectiveness of penicillin and by differences in clinical, physiological, cultural, and socioeconomic considerations across different patient populations and geographic settings. In addition, current diagnostic tests and tests-of-cure create challenges for clinical trial design. Various potential trial designs were discussed, focusing on subjects with different types and stages of disease. This summary of the workshop is presented to inform plans for future research, including clinical trials on alternatives to penicillin for the treatment of syphilis.