Human cytomegalovirus (HCMV) is the largest member of the family of human herpesviruses. The number of virus encoded proteins and the complexity of their functions in the life cycle of this virus are reflected in the size of its genome. There continues to be some controversy surrounding the exact protein coding capacity of the virus with estimates ranging from 160 open reading frames to more than 200 open reading frames. Very recent studies using mass spectrometry to determine the viral proteome suggests that the number of viral proteins may be even greater than previous estimates. The proteins of the virion capsid have readily identifiable homologous proteins in the capsid of the more extensively studied herpes simplex virus, likely because of similar capsid structure and assembly pathways. In contrast, the tegument and the envelope of HCMV contain a significant number of proteins that lack structural homology to proteins found in either α or γ-herpesviruses. This brief overview discusses some of the general features and possible functions of the HCMV virion structural proteins in the replicative cycle of this virus. © American Society for Histocompatibility and Immunogenetics, 2004. Published by Elsevier Inc.