Genital ulcers may be located on the vagina, penis, and anorectal or perineal areas and may be infectious or noninfectious. Herpes simplex virus is the most common cause of genital ulcers in the United States. A diagnosis of genital herpes simplex virus infection is made through physical examination and observation of genital lesions. The 2015 Centers for Disease Control and Prevention sexually transmitted disease guidelines provide strategies for the management of patients with genital ulcer disease. Specific testing includes a polymerase chain reaction test for herpes simplex virus; syphilis serology and darkfield microscopy or a direct fluorescent antibody test for Treponema pallidum; and/or culture for Haemophilus ducreyi in settings where chancroid is highly prevalent. Rarely, cases of Epstein-Barr virus may present with genital ulcers. Syphilis and chancroid cause genital ulcers and are mandatory reportable diseases to the local health department. In some cases, no pathogen is identified. It is important to consider noninfectious etiologies such as sexual trauma, psoriasis, Behçet syndrome, and fixed drug eruptions. Genital ulcers are symptomatic by definition, and the U.S. Preventive Services Task Force recommends screening for syphilis infection for those at risk, early screening for syphilis infection in all pregnant women, and against routine serologic screening for genital herpes simplex virus infection in asymptomatic adolescents and adults, including those who are pregnant.