Bacillus Calmette-Guerin (BCG) is the only FDA approved first line therapy for patients with nonmuscle invasive bladder cancer. Since the turn of the 20th century BCG has been used as a vaccine for protection against Mycobacterium tuberculosis (Mtb) and has also been found to have protection against nontuberculosis related pathogens. Recently the role of "trained immunity" has been identified as a possible mechanism for BCG vaccine-mediated immunity to Mtb. Similarly, BCG has been used as an immunotherapy for bladder cancer for more than 40 years, and the underlying mechanisms for BCG-mediated anti-tumor activity is poorly characterized. Several studies have shown that multiple immune pathways contribute to the immune response, and efficacy of intravesicle BCG as a cancer therapy. It is vital that we integrate our understanding of BCG as a vaccine and as a cancer therapeutic to facilitate design of future studies in order to maximize the immunotherapeutic potential of BCG. In this review we will outline the role of BCG as a vaccine, the known immune pathways that are activated by intravesical BCG and outline a potential clinical study integrating BCG vaccination prior to intravesicle instillation of BCG.