Tobacco consumption has become a major public health issue, which has motivated studies to identify and understand the biological processes involved in the smoking behavior for prevention and smoking cessation treatments. CYP2A6 has been identified as the main gene that codifies the enzyme that metabolizes nicotine. Many alleles have been identified after the discovery of CYP2A6, suggesting a wide interethnic variability and a diverse smoking behavior of the allele carrying individuals. The main purpose of this review is to update and highlight the effects of the CYP2A6 gene variability related to tobacco consumption reported from diverse human populations. The review further aims to consider CYP2A6 in future studies as a possible genetic marker for the prevention and treatment of nicotine addiction. Therefore, we analyzed several population studies and their importance at addressing and characterizing a population using specific parameters. Our efforts may contribute to a personalized system for detecting, preventing and treating populations at a higher risk of smoking to avoid diseases related to tobacco consumption.