Bacillus Calmette-Guérin (BCG) is one of the world’s oldest and most widely used vaccines. It was developed in the early 20th century to provide protection from tuberculosis. Surprisingly, this vaccine protects not only against tuberculosis but also reduces the risk for various other infections, through a mechanism called trained immunity. A new study led by Christoph Bock and Mihai Netea found that epigenetic cell states predict whether or not an individual profits from the “wake-up call” to the innate immune system that is provided by the BCG vaccine. This discovery contributes to the development of future therapeutics that induce protective trained immunity.