Chronic intravenous drug self-administration in rodents is a useful procedure for predicting the abuse liability of novel drugs in humans, for evaluating candidate treatments for drug abuse and dependence, and for studying the biological basis of addiction. Despite the technical challenge in achieving chronic self-administration behavior in the mouse species, researchers are increasingly using genetically engineered mice to investigate the role of specific genes in abuse-related effects of drugs. This review focuses on recent technical innovations as well as theoretical considerations for comparing intravenous (i.v.) drug self-administration behavior between mouse strains, including mice with targeted mutations. Part I of the present article describes techniques for successfully conducting self-administration studies in mice, including advantages, disadvantages and possible implications of employing various experimental approaches. Part II provides a review of recent data that address how the genetic background on which mutations are expressed may influence results from gene-targeting studies.