We have undertaken a series of investigations aimed at improving the precision of diagnosis and classification of human lymphoproliferative disease. Our approach is based on determination of lineage and differentiation through the use of monoclonal antibodies, flow cytometry and molecular genetics. As a result of these studies, we have outlined, in detail, the molecular genetic basis of the diagnosis of lymphoproliferative disease. We have proven that monoclonality is not pathognomonic of malignancy since some nonmalignant lymphoid proliferations are clonal. In further investigations of the application of molecular genetics to the diagnosis of clonality in lymphoproliferations, we have discovered a critical limitation of the human T-cell gamma gene and have characterized the restricted repertoire of the gamma gene on polyclonal T cells. Our investigations of precursor T-cell (lymphoblastic) neoplasms have revealed a recapitulation of normal early T-cell ontogeny. Clonal precursor T-cell neoplasms exhibit developmental orchestration of the rearrangement and expression of genes encoding antigen recognition in human T cells. We have developed mutants of pre-T cell lines which do not transcribe the T-alpha gene and have lost expression of the T3 complex present in the parental cells. Despite advances in the cellular origins of non-Hodgkin's lymphoproliferative disease, the lineage and clonal derivation of Hodgkin's disease remains largely unknown. We have prepared highly enriched Hodgkin's cell suspension from several patients and have discovered evidence of immunoglobulin gene rearrangements in the Reed-Sternberg fractions. This seminal finding provides a foundation for analysis of the molecular biology of Hodgkin's disease.