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What Is Known and Objective: Pharmacogenomics holds promise in smoking cessation because of its potential to shed light on the complexity of drug metabolism and improve treatments using therapeutic agents. The cytochrome P450 2B6 gene (CYP2B6) encodes CYP2B6 enzyme that has been found to mediate the hydroxylation of bupropion, a smoking cessation aid. CYP2B6 exhibits a range of polymorphic variants that alter the pharmacokinetics and pharmacodynamics of bupropion. Genetic variations in CYP2B6 may influence the risk of adverse effects or efficacy of treatment with bupropion. The objective of this review was to investigate the influence of pharmacogenomics on smoking cessation therapy., Methods: A thorough literature search was conducted on PubMed, SCOPUS and EMBASE using keywords related to bupropion, smoking cessation, pharmacogenomics and CYP2B6. Research and review articles, case reports and clinical and preclinical studies pertinent to the research topic were identified, evaluated and summarized. Cited articles within the above-mentioned sources also provided pertinent information., Results: There is strong literature evidence to prove that CYP2B6 polymorphisms affect pharmacokinetic and pharmacodynamic properties of bupropion, thus affecting the therapeutic outcome of smoking cessation therapy., What Is New and Conclusions: Complete understanding of pharmacogenetic variation of bupropion pharmacokinetics and pharmacodynamics will be beneficial for designing safer and more personalized smoking cessation therapy with improved outcomes., (© 2018 John Wiley & Sons Ltd.)