There is an unmet need for new approaches to treat prostate cancer beyond hormonal deprivation and chemotherapy. Using immunotherapy to focus immune responses on prostate cancer antigens appears to be a valid therapeutic approach. Several immunotherapeutic agents are being developed employing a variety of approaches. In recent years, Listeria monocytogenes (Lm)-LLO immunotherapy has been well tolerated in early clinical studies and is currently being evaluated in the clinic for HPV-associated dysplasia and malignancies such as recurrent/refractory cervical cancer, cervical intraepithelial neoplasia (CIN) 2/3, and head and neck cancer. Lm is a strong stimulator of both innate and cellular immune responses due to its unique life-cycle. Attenuated Listeria-based Lm-LLO immunotherapy secreting human prostate specific antigen (PSA) (ADXS31-142) has been shown to cause the therapeutic regression of PSA-expressing tumors in mouse models. The therapeutic effect of ADXSD31-142 on tumor regression is associated with the generation of PSAspecific T cells and subsequently, their infiltration in the tumor microenvironment, accompanied by the reduction of regulatory T cells (CD4+CD25+Foxp3+) within the tumors. Further development is underway to advance ADXS31-142 Lm- LLO immunotherapy into the clinic for the treatment of castration resistant prostate cancer.