Many patients with symptoms and signs compatible with a connective tissue disease have features consistent with more than one type of rheumatic disease. Special attention has been drawn to a subset of antinuclear antibody–positive patients who have high titers of RNP autoantibodies and overlapping features of SLE, scleroderma, rheumatoid arthritis and inflammatory myositis. Swollen or puffy hands are a common early feature of disease. Raynaud phenomenon, arthralgias, and myalgias are common. Unlike patients with SLE, renal or central nervous system disease is uncommon. A key reason to identify this subset of patients is that pulmonary hypertension and interstitial lung disease are major causes of mortality, and regular screening for these manifestations is required. Some patients have features of more than one connective tissue disease (eg, rheumatoid arthritis and SLE, SLE and scleroderma) in the absence of high-titer anti-RNP antibodies and are referred to as having an “overlap syndrome.” Treatments are guided more by the distribution and severity of patients’ organ system involvement than by therapies specific to these overlap syndromes.