Hematologic malignancies were the first diseases in clinical oncology for which the potential of harnessing the immune system as targeted therapy was unequivocally demonstrated. Unfortunately, the use of this highly efficacious modality has been limited to only a subset of patients and diseases because of immune-mediated toxicities resulting from incomplete specificity, and disease-specific determinants of sensitivity versus resistance to immune effector mechanisms. Recent studies, however, have begun to elucidate the molecular basis of the observed clinical effects allowing the rational development of next generation of immunotherapeutic combinations. We discuss here cancer antigen targets in hematologic malignancies and the specific approaches to induce immunity being pursued, the importance of modulating the host immunoregulatory environment, and the special features of immunological monitoring in clinical investigation. The hematologic malignancies represent an ideal setting for the development of immunotherapy due to logistical, clinical monitoring, and disease biology factors and may represent an exemplar for immune-based treatment in other cancer types.