Small ubiquitin-like modifier proteins are members of the ubiquitin-like protein family. Covalent modification of proteins by SUMO affects their activity, intracellular localization, stability, and interaction with other proteins and DNA. The cellular Reversine SUMOylation pathway, which is largely analogous to the ubiquitin modification pathway, regulates many important cellular processes. In brief, SUMO precursors are C-terminally processed to create an active form, which is activated by the formation of a thioester bond between the C-terminal glycine residue of SUMO and the active cysteine reside of a heterodimeric E1 activation enzyme, which comprises SAE1 and SAE2. SUMO is then transferred to the E2 conjugation enzyme, Ubc9, via an analogous thioester bond, and finally to the lysine residue of a substrate. SUMO E3 ligases, such as PIAS proteins, RanBP2, and Pc2, help transfer SUMO from Ubc9 to the substrate. Both Ubc9 and the E3 ligases appear to control the substrate specificity of SUMOylation. SUMO can be released from a substrate through cleavage by proteases called SENP; therefore, SUMOylation is reversible. Proteins also can interact with SUMO non-covalently through a SUMO-interacting motif, which is characterized by a stretch of hydrophobic residues, often flanked by acidic residues. Evidence is accumulating that the cellular SUMOylation pathway plays a regulatory role in infection by many different viruses, including human cytomegalovirus . HCMV is an opportunistic pathogen that can cause congenital disease and produces serious disease complications in immunocompromised individuals. During the lytic cycle of HCMV infection, viral genes are expressed in a cascade fashion with immediate-early, early, and late phases. The 72-kDa IE1 and 86-kDa IE2 proteins are the major IE proteins that regulate activation of viral genes and modulate host cell functions. Both IE1 and IE2 are modified by SUMO during HCMV infection. IE2 is a strong transactivator that interacts with numerous cellular transactivators and is essential for early and late viral gene expression. IE2 is modified by SUMO at two lysine residues, K175 and K180. In transfection assays, SUMOylation of IE2 enhances the transactivation of diverse cellular and viral promoters by IE2. Consistently, transactivation activity of IE2 has been correlated with its degree of SUMOylation. IE2 directly binds to Ubc9 and PIAS1. Mutation of both K175 and K180 in a laboratory strain and a clinical isolate caused a modest decrease in virus replication, indicating that IE2 SUMOylation promotes the virus lytic cycle in the context of virus infection. However, the effect of IE2 SUMOylation on viral growth appears to depend on the virus strains and infection conditions, since similar mutations in another laboratory strain did not significantly affect viral growth. IE2 also non-covalently interacts with SUMO through a SIM adjacent to the SUMO conjugation sites. This SIM is necessary for efficient SUMOylation and transactivation activity of IE2, thereby promoting viral growth.