Molecular diagnostic assays have become routine in the evaluation of lymphoid malignancies. Both Southern transfer and polymerase chain reaction (PCR) technologies are used to assess for B- and T-cell clonality, the presence of rearrangements involving protooncogenes such as bcl-1 and bcl-2, and the monitoring of minimal residual disease. We review the fundamentals of B- and T-cell ontogeny as well as the basic principles of the Southern transfer and PCR assays and their applications to the diagnosis of lymphoid malignancies.