Myositis-overlap syndromes are characterized by a heterogeneous group of clinical syndromes of which many are closely linked with specific autoantibodies. Clinical and laboratory-based research into this fascinating group of syndromes have given us clues in elucidating the role of immunogenetic, environmental influences on the etiopathogenesis of autoimmune disease. Patients positive for anti-snU1 RNP antibody often present with a constellation of "autoimmune-related" clinical features, often not fulfilling the diagnostic criteria for a single disease entity. Controversy remains as to whether this represents a single disease entity, namely mixed connective tissue disease, or an undifferentiated autoimmune rheumatic/overlap syndrome. Anti-PM-Scl antibodies are linked with myositis-scleroderma overlap and generally tend to follow a benign course, often responding well to minimal immunosuppression. More recently the number of anti-tRNA synthetase antibody-associated overlap syndromes has expanded; antibodies to the autoantigen histidyl-tRNA synthetase (Jo1) being the commonest and best characterized. Patients with these antibodies often have severe interstitial lung disease and the poorest prognosis, often necessitating aggressive immunosuppressive therapy.