<p>Post-translational protein modifications by the small ubiquitin-like modifier (SUMO) family have been shown to regulate immune cells in the context of infection, autoimmunity and, more recently, cancer. Recent clinical trials investigating sumoylation inhibition as a therapeutic approach for cancer have established that sumoylation has important immune modulatory effects. Sumoylation suppresses transcription factors in innate immune cells and in cytotoxic T cells through the direct modification of these factors, which leads to the recruitment of transcriptional repressor complexes containing histone deacetylases. By contrast, in regulatory T cells and T helper 17 cells, sumoylation of transcription factors can enhance transcriptional activity by recruiting transcriptional coactivators. Sumoylation is also involved in the repression of <i>IFNB1</i> and endogenous retroviruses and is therefore important for regulating interferon expression. A central theme from literature is that the sumoylation of a group of proteins, instead of a single target, collectively contributes to the regulation of various immune processes. In this Review, we consider how these studies provide scientific basis for future exploration of SUMO-mediated immune modulation for the treatment of cancers and autoimmune disorders.</p>