Historically, immune-based therapies have played a leading role in the treatment of hematologic malignancies, with the efficacy of stem cell transplantation largely attributable to donor immunity against malignant cells. As new and more targeted immunotherapies have developed, their role in the treatment of hematologic malignancies is evolving and expanding. Herein, we discuss approaches for antigen discovery and review known and novel tumor antigens in hematologic malignancies. We further explore the role of established and investigational immunotherapies in hematologic malignancies, with a focus on personalization of treatment modalities such as cancer vaccines and adoptive cell therapy. Finally, we identify areas of active investigation and development. Immunotherapy is at an exciting crossroads for the treatment of hematologic malignancies, with further investigation aimed at producing effective, targeted immune therapies that maximize antitumor effects while minimizing toxicity.