Active immunotherapy has shown great promise in preclinical models for the treatment of infectious and malignant disease. Yet, these promising results have not translated into approved therapies. One of the major deficits of active immunotherapies tested to date in advanced clinical studies has been their inability to stimulate both arms of the immune system appropriately. The interest in using recombinant bacteria as vaccine vectors for active immunotherapy derives in part from their ability to stimulate multiple innate immune pathways and, at the same time, to deliver antigen for presentation to the adaptive immune system. This review will focus on the development of live-attenuated and killed strains of the intracellular bacterium Listeria monocytogenes for treatment of chronic infections and cancer. Early clinical trials intended to demonstrate safety as well as proof of concept have recently been initiated in several indications. Advances in molecular engineering as well as successes and challenges for clinical development of L. monocytogenes-based vaccines will be discussed.