The success of immune-mediated therapies has encouraged studies on passive and active immunotherapy in leukemia and lymphoma. This review outlines the impact of increasing insights from basic immunology studies on the potentiation of effective immune responses and the identification of new antigens as targets for antibody (Ab)-targeted therapies. The principles of treatment in leukemia and lymphoma based on current knowledge on the classification of hematologic malignancies are reviewed, and discussed in the context of a rationale to implement new Ab-targeted immunotherapeutic approaches. An update is provided on the use of Ab-targeted therapies in clinical trials with emphasis on new emerging strategies to further expand the successful field of immunotherapy in leukemia and lymphoma.