BCG is not only used as a vaccine for tuberculosis (TB) prevention but also as an immunotherapy against bladder cancer. In addition to this, administration of BCG has widely documented protective effects against (a) nontuberculous mycobacterial and other bacterial infections, (b) viral infections, (c) parasitic and fungal infections, (d) autoimmune diseases such as Type I diabetes, (e) cancers other than bladder cancer, and (f) overall neonatal mortality. These diverse protective effects of BCG have been attributed to the ability of BCG to induce epigenetic and metabolic changes that confer nonspecific memory or to “train” innate immune cells against secondary heterologous stimuli. Trained innate immune responses appear to be short-lived (months to years) relative to classic T- and B-cell adaptive immunity, and mechanisms underlying immune training have been identified in both central compartments (bone marrow) and the peripheral blood and lymphatic system. In this chapter, we shall discuss the current knowledge associated with BCG-mediated heterologous protection and the existing knowledge gaps in the literature. Future research demands a comprehensive understanding of the underlying molecular mechanisms of BCG activity to identify biological pathways that may be targeted for improved disease outcomes.