The application of DNA probes to demonstrate clonal rearrangements of the immunoglobulin heavy and light chain and T cell receptor beta chain gene loci by Southern blot hybridization analysis has led to significant advances in our ability to diagnose, classify and investigate the lymphoproliferative disorders. This approach has allowed us to conclusively determine the B or T cell lineage derivation and the clonal nature of the vast majority of lymphoid neoplasms, resulting in a new level of understanding of the biology of lymphoid neoplasia. Further application of these DNA probes to other poorly defined and controversial lymphoproliferative disorders should clarify their nature as well. Eventually, antigen receptor gene rearrangement analysis may become routinely employed in diagnosing lymphoid malignancies, monitoring the effects of chemotherapy, detecting early subclinical relapses and identifying disease progression, especially with respect to detecting the emergence of new clonal populations.