The bacillus Calmette-Guérin (BCG) is a live, attenuated vaccine from Mycobacterium bovis obtained by Albert Calmette and Camille Guerin through 230 in vitro passages between 1908 and 1921. This chapter presents clinical applications of BCG such as tuberculosis, leprosy, asthma and other hypersensitivity diseases, Type 1 diabetes, multiple sclerosis, and cancer. BCG can be described as a “double-acting tool” because its own immunogenicity produces a preventive effect in a variety of diseases and may trigger a number of autoimmune phenomena. An acute inflammatory polyarthritis with skin maculopapular rash was reported in a healthy woman following intradermal BCG. Side effects such as granulomatous pneumonia and hepatitis are reported without sufficient data to support the possible link with intravesical BCG and the autoimmune mechanism. Even the kidney may be the target of hypersensitivity reaction to intravesical BCG, which can induce an interstitial nephritis with non-necrotizing, sterile granulomas responsive to steroid therapy