An upregulation of cellular signaling pathways is observed in multiple cell types upon human cytomegalovirus (HCMV) infection, suggesting that a global feature of HCMV infection is the activation of the host cell. HCMV initiates and maintains cellular signaling through a multitiered process that is dependent on a series of events: (1) the viral glycoprotein ligand interacts with its cognate receptor, (2) cellular enzymes and viral tegument proteins present in the incoming virion are released and (3) a variety of viral gene products are expressed. Viral-mediated cellular modification has differential outcomes depending on the cell type infected. In permissive cell types, such as diploid fibroblasts, the upregulation of cellular signaling pathways following infection can initiate the viral gene cascade and promote the efficient transcription of multiple viral gene classes. In other cell types, such as endothelial cells and monocytes/macrophages, the upregulation of cellular pathways initiates functional host changes that allow viral spread to multiple organ systems. Together, the modification of signaling processes appears to be part of a thematic strategy deployed by the virus to direct the required functional changes in target cells that ultimately promote viral survival and persistence in the host.