Clonality is regarded as an important diagnostic feature of B-cell lymphomas, but until recently the clonality of T-cell proliferations could not be directly determined. Elucidation of the genetic events in lymphocytic differentiation has led to the development of an assay for clonality in both B- and T-cell infiltrates. Clonal rearrangement of the immunoglobulin or T-cell receptor genes can be detected by the Southern blot technique. Such rearrangements provide evidence of clonal proliferation, which, in the proper context, can be regarded as a sign of malignancy. The presence of gene rearrangements in poorly differentiated neoplasms may serve as evidence of hematopoietic differentiation, and the pattern of such rearrangements may point to either T- or B-cell lineage. Specific applications to dermatopathology include the evaluation of skin biopsy specimens for cutaneous lymphoma, evaluation of peripheral blood specimens for detection of Sézary's syndrome, and evaluation of lymph nodes and blood for the staging of mycosis fungoides.