Although human cytomegalovirus (HCMV) rarely causes overt disease in healthy individuals, the virus can be a serious, even life-threatening problem in immunosuppressed or immune-deficient patients and in the setting of maternofetal primary infection. In recent years knowledge about HCMV pathogenesis has increased significantly. Identification of the cell types infected by HCMV in vivo has demonstrated that monocytes/macrophages and endothelial cells are key elements both in latent and acute infection with HCMV. Both cell types can be involved in systemic spread of virus and specific organ disease. While it has been demonstrated that differentiation of monocytes into macrophages renders these cells permissive to productive HCMV infection, there is presently limited knowledge about the pathogenesis of HCMV in endothelial cells (ECs). These cells represent the physiological interface between blood and tissues, display heterologous phenotypes, and are functionally variable, depending on their respective microanatomic environment. Microvascular ECs are the site of monocyte transmigration into organ tissues and therefore are likely to regulate the activation state of infected monocytes. Recently, macrovascular endothelium is receiving increasing attention due to its possible involvement in atherogenesis. In this overview we present recent findings on the role of monocytes/macrophages and endothelial cells in HCMV infection.