Cutaneous manifestations of systemic connective tissue diseases, such as scleroderma and its variants, polymyositis, and dermatomyositis, often prompt early dermatologic consultation. Indirect immunofluorescent autoantibody determinations using tissue culture substrates are initial screening tests that are highly positive in the majority of patients with scleroderma and its variants, but are less frequently positive in patients with polymyositis and dermatomyositis. When combined with second-level analyses for the multiplicity of precipitin autoantibodies that have been defined in both these major classes of rheumatic diseases, most autoantibodies of both diagnostic and prognostic significance can be defined efficiently and cost-effectively. The major autoantibody specificities characteristic of these connective tissue diseases are summarized in this article, with emphasis on current concepts of their clinical molecular, and possible pathogenetic significance.