Certain autoantibodies are characteristic of autoimmune disease manifestations and contribute to organ pathology. The presence of high-titer antibodies to U1-RNP are associated with mixed connective tissue disease, although these antibodies may also be present in systemic lupus erythematosus and systemic sclerosis. However, the role of antibodies to U1-RNP in the pathogenesis of connective tissue disease remains unclear. Data from recent experimental studies promote the hypothesis that U1-RNP antibodies participate in both innate and adaptive immune responses, implicating them in the pathogenesis of connective tissue disease.