Gene therapy offers many new and exciting treatment strategies for patients with hematologic malignancies. Through the transfer of genes into hematopoietic stem cells, one can reduce the sensitivity of myeloid cells to chemotherapy. Donor T cells can be modified to become sensitive to otherwise nontoxic prodrugs, allowing for their safer use as effectors in graft-versus-leukemia immune reactions following allogeneic transplantation. Neoplastic cells also may be modified to enhance their sensitivity to various drugs. Finally, neoplastic cells can be modified to enhance their immunogenicity using genes that encode immune stimulatory cytokines or cell surface proteins. Recent studies, for example, indicate that the stealth-like phenotype of leukemia cells can be reversed through transfer of genes such as the one encoding CD154, the ligand for CD40. A phase I clinical trial using autologous CD154-transduced leukemia cells as a cellular vaccine has provided encouraging results. Indeed, we may soon enter an era of effective gene therapy for hematologic malignancies.