Leukemias and lymphomas can now be classified according to the particular immunoglobulin, T-cell receptor, or growth-affecting genes they are expressing. Recognition of the structural alterations of lymphoid DNA has been used to identify neoplasms of previously uncertain lineage, to aid in diagnosis, and to define the state of differentiation of the neoplasm. We have developed a procedurally simple, rapid turnaround technique for using tumor-specific gene alterations as tumor-specific markers. Probes can be constructed that will recognize only the gene expressed in the tumor and not those in any of the normal cells when used with tissue in situ hybridization. We demonstrate the application of direct sequencing of a specific gene of interest from total RNA from a patient with multiple myeloma. A probe is then generated from this sequence and applied directly to patient material.