Despite major progress in treating hematologic malignancies and, to a lesser extent, metastatic solid tumors, much work remains ahead. With the anticancer potential of immunotherapy not yet fully exploited, patients with leukemia, malignant lymphoma, and other hematologic malignancies for which high-dose chemoradiotherapy is frequently recommended in conjunction with stem cell transplantation (SCT) can now benefit from the advantages of immunotherapy mediated by cytokines or alloreactive donor lymphocytes, while minimizing procedure-related toxicity and mortality. The feasibility of applying allogeneic cell-mediated immunotherapy in conjunction with allogeneic SCT following reduced-intensity conditioning, with minimal toxicity and no serious transplant-related complications, makes it possible to undertake such procedures on an outpatient basis as well as to offer an option for cure to elderly individuals and patients with less than optimal performance status. Being well tolerated, reduced-intensity transplants also offer a chance for cure to patients with otherwise resistant leukemia and malignant lymphoma who have relapsed after autologous SCT. Thus, the traditional obstacle of very high transplant-related toxicity and mortality due to multiorgan failure from cumulative toxicity of multiple anticancer agents and radiation therapy is overcome. Although immunotherapy mediated by allogeneic lymphocytes can be most effective, the immune potential of donor lymphocytes should be maximized by nonspecific or specific activation in vitro or in vivo, or both, for more effective eradication of resistant tumor cells, including in patients with bulky disease. More important is the challenge to target donor lymphocytes to the tumor and minimize their capacity to induce responses against normal host tissues, which frequently results in severe acute and chronic graft-versus-host disease (GVHD). Alternatively, donor lymphocytes should be eliminated as soon as tumor eradication is completed, or as soon as severe GVHD becomes prohibitive. Based on available experience, clinical application of innovative therapy, especially at the stage of minimal residual disease (MRD), may open new horizons for the treatment of malignancies considered until recently to be incurable. The feasibility of controlling cancer by targeted chemotherapy, best illustrated by the phenomenal activity of imatinib in patients with chronic myelogenous leukemia and, more recently, in gastrointestinal stromal tumors (including in patients fully resistant to all known anticancer agents) suggests that in the future, tumor-specific chemotherapy may represent the ultimate goal for achieving a stage of MRD with minimal multiorgan toxicity. Together, the combination of immunotherapy and targeted chemotherapy may provide the most logical approach for making real progress in controlling resistant hematologic malignancies and metastatic solid tumors.