New principles are discussed for the classification of the diffuse collagen diseases, particularly the mixed connective tissue disease (MCTD), with clinical and historical explanation. Emphasis in classification has shifted from a concern with tissue pathology to serologic anomalies, which may involve eleven different antigens, many from human cell nuclei. New serologic tests, such as the ribonucleoprotein (RNP) antibody test, may be superior to the well-known fluorescent antinuclear antibody (ANA) studies for diagnosis and follow-up of diffuse collagen diseases. Functional clinical studies, such as esophageal motility, gas exchange in the lung, and major joint mobility, which may appear early in MCTD, are more important to diagnosis than anatomic studies of late-developing lesions.