The epidemiology of oral and genital herpes has dramatically changed over the past decade. Herpes simplex virus-1, traditionally associated with oral herpes, is now implicated in an increasing percentage of genital herpes cases. The possibility of “autoinoculation” (or self-infection) of anatomic sites other than that of the primary infection has been recognized. New methods of suppression therapy are being examined. These changes have led to a revision in the recommendations by the Centers for Disease Control and Prevention (CDC). This review discusses herpes infections of the oral and genital mucosa and the suggested approach to the infected patient who presents in the emergency department. Specific attention is given to the CDC’s 2006 guidelines for the treatment of sexually transmitted diseases.