Bacille Calmette-Guérin (BCG) is an attenuated strain of Mycobacterium bovis. It is derived from 231 in vitro passages conducted at the Pasteur Institute of Lille, France. The first BCG vaccination was performed 100 years ago, and to this day, it remains the only licensed vaccine against tuberculosis (TB). Although it was developed exclusively for conferring protection against tuberculosis, BCG has also shown beneficial effects in several other therapeutic roles, including its use as an immunotherapeutic agent for superficial urothelial carcinoma and melanoma skin cancer. It has also demonstrated potential application as a vaccine vector for the delivery of heterologous antigens and immunological mediators, such as cytokines. Thus, the development of recombinant strains of BCG (rBCG) have been widely explored. Additionally, BCG has demonstrated potential application as an immunotherapeutic agent for autoimmune, allergic, and neurodegenerative diseases, which has been attributed to the induction of memory in innate immune cells (a.k.a. trained immunity). In this review, we provide an update on the immunobiological and immunological aspects involved in bacillus-host interactions in the context of BCG.