Gene therapy for patients with hematologic malignancies, particularly chronic lymphocytic leukemia (CLL), have focused on transducing primary leukemia cells with a virus vector to express immune-stimulating genes which can induce and propagate a productive and clinically significant immune response against the malignant cells. A variety of replication-defective vectors has been studied to transduce genes for cytokines and function-associated surface molecules. Active vaccines have been developed in vitro, and their activity has been confirmed in clinical trials. Ongoing work aims to optimize this strategy and to identify the appropriate and optimal patient groups in which to apply vaccine therapy. Clinical trials also have provided insight into unexpected alternative mechanisms through which these strategies might provide a clinical benefit.