For decades Listeria monocytogenes has been used as a model of host-disease immunology, and a considerable body of knowledge has been amassed regarding the complex immune response to L. monocytogenes. Attenuated strains of L. monocytogenes are currently being assessed as therapeutic bacterial vectors to present tumor-associated antigens to the immune system for the clinical treatment of cancer. L. monocytogenes immunotherapy utilizes many synchronous and disparate action mechanisms that stimulate innate and cell-mediated adaptive immunity while reducing immunosuppressive influences in the tumor microenvironment. Other effects not typically associated with immunotherapy include the stimulation of myeloid hematopoiesis and vascular changes that enable chemotaxis. Preliminary clinical results using L. monocytogenes bearing the HPV oncogene E7 indicate good tolerability and a strong efficacy signal, warranting further development. This article reviews the current status of L. monocytogenes as a cancer immunotherapeutic and the complex immune responses that underlie L. monocytogenes immunotherapy.