The replication cycle of the human cytomegalovirus (HCMV) is characterized by the expression of immediate early (IE), early (E), and late (L) gene regions. Current antiviral strategies are directed against the viral DNA polymerase expressed during the early phase of infection. The regulation of the IE-1 and IE-2 gene expression is the key to latency and active replication due to their transactivating and repressing functions. There is growing evidence that the pathogenic features of HCMV are largely due to the abilities of IE-1 and IE-2 to transactivate cellular genes. Consequently, current drugs used to inhibit HCMV infection would have no impact on IE-1 and IE-2-induced effects that are produced before the early phase. Moreover, when HCMV DNA replication is inhibited, IE gene products accumulate in infected cells causing disturbances of host cell functions. This review summarizes the biological functions of HCMV-IE gene expression, their relevance in pathogenesis, as well as efforts to develop novel treatment strategies directed against HCMV-IE expression.