Bacillus Calmette-Guérin (BCG) was originally developed as a vaccine against tuberculosis and is estimated to be the most widely used vaccine in human history. Its extensive and worldwide use has allowed observational and epidemiological evidence that points toward the promising heterologous effects of BCG across a wide range of diseases. Several studies have already demonstrated the impact of BCG immunization in reducing all-cause mortality by inducing protection against infections with nonrelated pathogens. The beneficial effects of BCG immunization have also been described for other diseases such as cancer, autoimmune, metabolic, and neurodegenerative diseases. This heterologous protection conferred by BCG administration has been attributed to BCG’s ability to modulate innate and adaptive immunity, resulting in long-term functional reprogramming of innate immune cells—trained immunity. The administration of BCG is already clinically approved as an immunotherapy to treat some non-muscle-invasive bladder cancers and as an adjuvant therapy against cutaneous metastatic melanoma. More research is still needed to elucidate further the cellular and molecular mechanisms by which BCG exerts its heterologous effects in different diseases, which may contribute to its integration as a therapeutic tool into more diverse therapeutic approaches.