BCG, Bacillus Calmette-Guérin, designed to protect against tuberculosis, is the oldest vaccine still in use. Since 1921, more than 3 billion children have received BCG which makes it also the most widely used vaccine so far. BCG is a live attenuated Mycobacterium bovis bacillus obtained after 230 passages over 13 years of continuous culturing. After its first use in humans, BCG has been distributed throughout the world, which has resulted in the generation of more than a dozen BCG substrains, varying in genetic makeup and potentially in biological properties. BCG has also shown nonspecific properties and appears to protect against heterologous infections and all-cause mortality. It is one of the most effective medications for the treatment of non-muscle-invasive bladder cancer and may be useful for the treatment of type 1 diabetes and potentially neurodegenerative diseases. The mechanisms of protection against tuberculosis and other diseases are not fully understood and are currently being investigated in many laboratories. Furthermore, improved strains through genetic engineering are being developed, and some have entered clinical evaluation. Whether they will ultimately replace BCG remains an open question, and it is likely that BCG still has many secret doors to be opened over the next century.