Small ubiquitin-like modifier (SUMO) proteins, as a subgroup of post-translational modifiers, act to change the function of proteins. Through their interactions with different targets, immune pathways, and the responses they elicit, can be affected by these SUMO conjugations. Thus, both a change to protein function and involvement in immune pathways has the potential to promote an efficient immune response to either a pathogenic challenge, or the development of an imbalance that could lead to an autoimmune-based disease. Also, a variety of changes such as mutations and polymorphisms can interfere with common functions of these modifications and move an effective immune response in the direction of an autoimmune disease. The present review discusses the general characteristics of SUMO proteins and focuses on their involvement in rheumatoid arthritis as an autoimmune disease.