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 IFNB1 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.