The processes of somatic immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement that occur in lymphoid precursors provide insights into the pathogenesis and molecular analysis of lymphoid malignancies, in addition to the more universal molecular oncogenic mechanisms. Detection of lymphoid clonality can help distinguish polyclonal reactive disorders from clonal, predominantly, but not exclusively, malignant proliferations. Ig/TCR V-(D)-J polymerase chain reaction (PCR) amplification has largely replaced Southern blotting, and the techniques of PCR product analysis are evolving rapidly. V-(D)-J errors are often involved in genetic abnormalities leading to lymphoid malignancies, with consequent deregulated expression of the associated proto-oncogenes. Genetic abnormalities producing fusion transcripts and chimeric proteins are also frequent, particularly in acute lymphoblastic leukemia (ALL). A variety of molecular techniques, including reverse-transcriptase (RT)-PCR, Southern blotting, and fluorescence in situ hybridization (FISH) are finding an increasingly established place in the diagnosis, prognostic evaluation, therapeutic stratification, and follow-up of lymphoblastic leukemias, and it is likely that the same methods will be applied to non-Hodgkin's lymphoma (NHL) and to chronic leukemias.