This paper provides an overview of the literature which indicates that genetic factors regulate the use of alcohol and tobacco by humans. The methods used to make genetic assessments in humans and the results obtained are discussed. Studies using animals have been helpful in identifying simpler behavioral components of the dependence process that are regulated by genetic factors. An overview of the genetic methods used most often in animal studies is presented along with an in-depth discussion of how these methods have been useful in uncovering genetic influences on nicotine responses in animals. Data which indicate that genetic factors regulate brain nicotinic receptor numbers and response to nicotine are also included as examples of how genetic strategies have been useful in increasing our understanding of how genes may influence behavior.