The non-Hodgkins' lymphomas are a diverse group of malignancies with characteristic clinical and laboratory features. The routine evaluation of these lesions includes histologic and immunophenotypic analyses. In the small percentage of cases that pose diagnostic challenges, the algorithm can include molecular genetic studies to help render a diagnosis. Unique immunoglobulin heavy- and light-chain or T-cell-receptor gene rearrangements are used to establish clonality in B- and T-cell proliferations. Whereas clonality is usually a hallmark of a malignant process, the absence of clonality does not exclude malignancy. This is predicted on the disparate biology of the various lympho-proliferative processes and on the technical aspects of the tests used for their identification. As molecular genetic testing for gene rearrangements becomes commonplace in the clinical laboratory, the variety of methods for performing these tests has increased. Since molecular testing may be the deciding feature in making a diagnosis of malignancy, the purpose of this review is to discuss the advantages and problems of the polymerase chain reaction and Southern blot method in detecting immunoglobulin gene rearrangements in B cells. The added goal of this summary is to encourage the laboratorian to interpret these tests in the context of complete clinical and histologic data.