Anti-Ro52/tripartite motif-containing 21 (TRIM21) is a ubiquitous antibody found in a number of systemic autoimmune conditions including Sjögren's syndrome, systemic lupus erythematosus and systemic sclerosis, appearing in about half of these patients. Once coupled with its closely related antibody, anti-Ro60 as the anti-SSA antibody, anti-Ro52 is emerging as a unique antibody with direct pathogenic disease involvement and distinct clinical properties. As a result, recent attention has turned to this antibody and its clinical associations and utility. There is a suggestion of anti-Ro52 being associated with more clinical and laboratory markers of disease; however, marked disagreements occur about its association with various clinical entities such as interstitial lung disease and Raynaud's phenomena. Nevertheless, with a relative paucity of studies about these across the systemic autoimmunity paradigm, limited confidence can be invested in these conclusions. Although the antibody holds great potential as a biomarker, further studies examining its clinical utility are needed. This paper will review the mechanisms of Ro52 as an autoantigen and the clinical associations of anti-Ro52 in human autoimmunity.