With increased threat of terrorism, much attention is being directed toward readiness for biodefense. Smallpox virus, a deadly and much feared organism, is among possible bioterrorism agents. Herpesviruses, such as the one that causes chickenpox and shingles, produce skin lesions that may resemble those seen early in smallpox infection. Electron microscopy (EM) is a rapid and reliable method for differentiating poxviruses from herpesviruses. However, before becoming involved in the monitoring of potential smallpox cases, a laboratory must consider several issues, including expertise in virus identification, capacity for handling biohazards, and health and immune status of laboratory staff.