After nearly a century of use, BCG vaccines continue to generate controversy and confusion. Their ability to prevent tuberculosis in studies has been inconsistent. When they have been protective, no clear mechanism of action has been established. Furthermore, the existence of different BCG strains has been described since the 1940s. These strains vary according to several laboratory properties, which may or may not translate into a discernible effect on vaccination. With recent genomic comparisons, it is now clear that different BCG vaccine strains have evolved and differ from each other and from the original BCG first used in 1921. Some of these genetic alterations explain certain variations in laboratory properties of BCG. However, these mutations in BCG strains have yet to be shown to affect BCG-associated protection and/or adverse effects. Continuing research is attempting to assess the effect of these genetic alterations on properties of BCG strains, with the goals of suggesting the ideal BCG for vaccination and providing avenues for improvement on existing BCG vaccines.