Protein sumoylation is a post-translational-modification event, in which small ubiquitin-like modifier (SUMO) is covalently attached to protein substrates by a three-step process. Sumoylation has been suggested to regulate multiple cellular processes, including inflammation. Inflammation is initiated in response to pathogenic infections, but uncontrolled inflammatory responses can lead to the development of inflammatory disorders such as rheumatoid arthritis. Recent studies indicate that proinflammatory stimuli, such as tumor necrosis factor alpha and lipopolysaccharide, can activate PIAS1 [protein inhibitor of activated STAT1 (signal transducer and activator of transcription 1)] SUMO E3 ligase through a SUMO-dependent, inhibitor of kappaB kinase alpha (IKKalpha)-mediated phosphorylation event. Activated PIAS1 is then recruited to inflammatory gene promoters to repress transcription. These findings support a hypothesis that therapies targeting the PIAS1 SUMO ligase pathway might be developed for the treatment of inflammatory disorders such as rheumatoid arthritis and atherosclerosis.