Post-translational modification of proteins by phosphorylation, methylation, acetylation, or ubiquitylation represent central mechanisms through which various biological processes are regulated. Reversible covalent modification (i.e., sumoylation) of proteins by the small ubiquitin-like modifier (SUMO) has also emerged as an important mechanism contributing to the dynamic regulation of protein function. Sumoylation has been linked to the pathogenesis of a variety of disorders including Alzheimer's disease (AD), Huntington's disease (HD), and type 1 diabetes (T1D). Advances in our understanding of the role of sumoylation suggested a novel regulatory mechanism for the regulation of immune responsive gene expression. In this review, we first update recent advances in the field of sumoylation, then specifically evaluate its regulatory role in several key signaling pathways for immune response and discuss its possible implication in T1D pathogenesis.