The current antituberculosis vaccine, BCG, was derived in the 1920s, yet the mechanisms of BCG-induced protective immunity and the variability of protective efficacy among populations are still not fully understood. BCG challenges the concept of vaccine specificity, as there is evidence that BCG may protect immunized infants from pathogens other than Mycobacterium tuberculosis – resulting in heterologous or nonspecific protection. This review summarizes the up-to-date evidence for this phenomenon, potential immunological mechanisms and implications for improved childhood vaccine design. BCG induces functional changes in infant innate and adaptive immune compartments, encouraging their collaboration in the first year of life. Understanding biological mechanisms beyond heterologous BCG effects is crucial to improve infant protection from infectious diseases.