Bacillus Calmette-Guérin (BCG) was developed exactly 100 years ago, and it is still the only licensed tuberculosis (TB) vaccine and the most frequently administered of all vaccines worldwide. Despite universal vaccination policies in TB-endemic settings, the burden of TB remains high. Although BCG protects against Mycobacterium tuberculosis infection and TB disease, the level of protection varies greatly between age groups and settings. In this review, we present a historical perspective and describe the evidence for BCG's ability to protect against TB as well as the factors that influence protection. We also present the immunological mechanisms through which BCG vaccination induces protection, focusing on T cell, B cell, and innate immunity. Finally, we discuss several possibilities to boost BCG's efficacy, including alternative vaccination routes, BCG revaccination, and use of recombinant BCG vaccines, and describe the knowledge gaps that exist with respect to BCG's protection against TB.