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Immediate-early (IE) genes of human cytomegalovirus are the first genes expressed after the virus infects the cell. The most extensively characterized of the IE genes is the major IE gene region. Originating from this gene is a series of overlapping mRNAs which encode proteins that have common and unique domains. Functionally, at least three IE proteins, IE 72, IE 55, and IE 86, are responsible for regulation of viral promoters. These proteins interact to enhance and repress expression of the major IE promoter resulting in a coordinate regulation that affects the balance of IE gene expression. In addition, IE proteins interact with cell factors during regulation of viral gene expression to activate early promoters. Therefore, the coordinate regulation of IE genes and their corresponding proteins, by cellular proteins in the infected cell, is likely to be the single most important determinant influencing the outcome of human cytomegalovirus infection.