The influence of genetic variability on human immune responses has major implications for the understanding of disease mechanisms and host-pathogen interactions. Bacillus Calmette-Guérin (BCG) vaccine, which is given globally to protect against tuberculosis, has high variability in its protective efficacy against mycobacteria and its beneficial off-target (heterologous) effects. Single nucleotide polymorphisms (SNPs) are major cause of genetic variation and have been strongly associated with susceptibility to tuberculosis and outcomes following BCG immunotherapy for cancer. This review discusses the contribution of SNPs to the variability in mycobacterial-specific and off-target BCG responses, and the implications for this on development of novel TB vaccines and strategies to harness the beneficial off-target effects of BCG.