Histidyl-tRNA synthetase (HRS = Jo-1) represents a key autoantibody target in the anti-synthetase syndrome that is marked by myositis as well as extra-muscular organ complications including interstitial lung disease (ILD). Over the last 25 years, a wealth of clinical, epidemiological, genetic, and experimental data have collectively supported a role for Jo-1 in mediating deleterious cell-mediated, adaptive immune responses contributing to the disease phenotype of the anti-synthetase syndrome. Complementing these studies, more recent work suggests that unique, non-enzymatic functional properties of Jo-1 also endow this antigen with the capacity to activate components of the innate immune system, particularly cell surface as well as endosomal Toll-like receptors and their downstream signaling pathways. Combining these facets of Jo-1-mediated immunity now supports a more integrated model of disease pathogenesis that should lead to improved therapeutic targeting in the anti-synthetase syndrome and related subsets of idiopathic inflammatory myopathy.