The human cytomegalovirus (HCMV) can infect a remarkably broad cell range within its host, including parenchymal cells and connective tissue cells of virtually any organ and various hematopoietic cell types. Epithelial cells, endothelial cells, fibroblasts and smooth muscle cells are the predominant targets for virus replication. The pathogenesis of acute HCMV infections is greatly influenced by this broad target cell range. Infection of epithelial cells presumably contributes to inter-host transmission. Infection of endothelial cells and hematopoietic cells facilitates systemic spread within the host. Infection of ubiquitous cell types such as fibroblasts and smooth muscle cells provides the platform for efficient proliferation of the virus. The tropism for endothelial cells, macrophages and dendritic cells varies greatly among different HCMV strains, mostly dependent on alterations within the UL128-131 gene locus. In line with the classification of the respective proteins as structural components of the viral envelope, interstrain differences concerning the infectivity in endothelial cells and macrophages are regulated on the level of viral entry.