Human herpesvirus 6 (HHV-6) is a member of the Roseolovirus genus of the b-herpesvirus subfamily of human herpesviruses. HHV-6 infects virtually all children during the early years of life and, like other herpesviruses, establishes latency after primary infection. In immunocompromised hosts, especially transplant recipients, HHV-6 is able to reactivate and cause disease. There are two subtypes of HHV-6: type A and type B. The two subtypes share certain biological properties and a high level of sequence homology, but differ dramatically in their epidemiology. We have learned much about the epidemiology and clinical impact of HHV-6 in the decades since it was first identified, but many questions still remain. This update focuses on new findings regarding the epidemiology and clinical syndromes of HHV-6, especially as they pertain to primary infection, neurological disease, and the transplant setting. In addition, diagnostics and antiviral treatment are reviewed.