Autoimmune inflammatory myopathies, referred to as myositis, comprise a heterogeneous group of chronic inflammatory muscle diseases that present with various clinical phenotypes, histologic changes and autoantibodies, resulting in progressive inflammatory muscle damage and weakness. In up to 20% of myositis patients, particularly those with dermatomyositis, there is an association with cancer that is most frequently diagnosed within 1 year of presentation of myositis. Accumulating data show that autoantibodies in myositis target a specific group of intracellular molecules that are not muscle-specific in their expression. The striking association between autoantibodies recognizing ubiquitously expressed molecules and distinct clinical phenotypes suggests that the target tissues themselves might regulate and shape the phenotype-specific immune response in myositis. Studies indicate that changes in phenotype-specific autoantigens, such as altered structure, enhanced expression, and acquisition of adjuvant properties during various forms of cellular stress, apoptosis, and transformation, might be mechanistically important in this regard. This Review discusses these developments and highlights a central role of autoantigens themselves as a critical partner in driving autoimmune diseases, and the potential for their therapeutic manipulation. In addition, we will highlight insights that the cancer-autoimmunity interface in this group of diseases provides into the relationship between the anticancer immune response and autoimmune diseases.