Molecular methods of defining gene rearrangements and DNA alterations that effect gene expression offer additional insights into malignant transformation of lymphoid cells. The highly clonal nature of myeloma is revealed by characterization of the unique Ig and TcR rearrangements. Whereas detection by DNA blot hybridization requires 2-5% clonality, more recent methods of DNA analysis, such as the polymerase chain reaction (PCR), can now increase the sensitivity of detection by several orders of magnitude. With improvement in therapies to treat myeloma, the issue of detection of minimal residual disease may be an important consideration in clinical management of the disease. The unique combinations of immunoglobulin gene segments and additional nucleotide alterations at junctional regions can be determined, and DNA probes can be synthesized that are clone-specific (Figure 1). By combining PCR amplification with detection methods employing clone-specific probes, significant improvements in disease detection are possible. As we begin to understand the functional consequences of genetic alterations associated with growth promoting genes such as the oncogenes myc and ras, and their role in myeloma, more promising therapies may be devised.