Because initial reinforcement consequences set the stage for subsequent nicotine use, elucidation of the contribution of environmental and inherited factors is crucial to an understanding of nicotine dependence as well as of individual differences in susceptibility to cigarette smoking. A review of some recent animal research and laboratory studies of smokers and never-smokers suggests that vulnerability to nicotine dependence is related to high initial sensitivity to nicotine and that the development of acute pharmacodynamic tolerance in these individuals--particularly to effects of nicotine that are toxic or aversive--may be an adaptation for protecting homeostasis.