This chapter discusses pharmacogenetics in the context of substance abuse and dependence. Genetic factors are important contributors to risk for substance dependence. Some are specific to the substance (e.g., resulting in different euphoric effects by individual), and some are more general (e.g., personality features, like novelty seeking, antisocial personality, and so on, which may influence exposure to substances or the transition from substance use to dependence). If the set of all genetically influenced disorders is considered, some forms of substance dependence are uniquely influenced by pharmacogenetic factors. The chapter explores some of the mechanisms involved, and their implications for diagnosis, treatment, and research. Specific pharmacogenetic interactions relevant to the understanding of dependence on cocaine, opioids, and nicotine have either been demonstrated or proposed. The chapter presents examples relevant to each phenotype. Pharmacokinetic phenomena relevant to cocaine and nicotine dependence are also discussed.