Mixed Connective Tissue Disease (MCTD) was first described 35 years ago by Gordon C. Sharp and his colleagues. In the ensuing decades, a clearer understanding of the clinical and serologic features of MCTD has emerged. Classification criteria now exist to define MCTD for study purposes, the long-term outcome of the disease has been established, and novel genetic associations within the major histocompatibility complex on chromosome 6 and select regions on chromosome 3 have been identified. Studies on immune pathogenesis have made substantial progress in advancing our understanding of MCTD. In MCTD, there is a complex interaction of the innate and adaptive immune system that culminates in autoimmune disease. Antigenic structural modification occurring during apoptosis or other modifications of self antigens leads to an autoantigen driven immune process with innate immune activation, immunoglobulin G autoantibody production directed against select components of the spliceosome, B lymphocyte activation, and CD4 and CD8 T lymphocyte participation.