The assemblage of the human heavy chain Immunoglobulin variable region from VH/DH/JH subsegments and the light chain variables from V Lambda/J Lambda and V Kappa/J Kappa subsets was examined within human lymphoid neoplasms representing multiple phases of differentation. Mature B cells displayed the appropriate recombinations of heavy and light chain genes, whereas, most cells pursuing non-B cell pathways of development retained germline genes. An extensive study of the controversial "non-T, non-B" form of acute lymphocytic leukemias indicated that they represented a developmental series of B-cell precursors. They further revealed a hieararchy of immunoglobulin gene rearrangement in which heavy chain genes preceded light and Kappa rearranged before Lambda. This order was confirmed within normal Lambda-bearing B cells. Similarly lymphoid blast crises of chronic myelogenious leukemia correspond to B cell precursors and the clonally affected B cells in this disease are capable of sequential heavy and light chain rearrangements. Clonally unique immunoglobulin rearrangements served as tumor-specific markers not only allowing assignment of cellular origin but also providing a tool for early detection and serial examination of clonal B cells. Hairy Cell Leukemia was shown to be a committed B cell at the gene level, but unexpectedly displayed the Tac antigen which serves as a membrane receptor for T cell growth factor. This molecular genetic approach is thus providing insight into the origins of controversial malignancies as well as their capacity for differentiation and mechanisms of transformation.