Chronic tolerance to any drug of abuse traditionally has been thought critical to understanding drug dependence. This paper reviews research on chronic pharmacodynamic tolerance to nicotine in humans. An overview of tolerance and a discussion of methodological issues are first presented, followed by examination of cross-sectional comparisons of tolerance between groups differing in smoking history, as well as the few prospective studies of change in tolerance after quitting smoking. The relationship of nicotine tolerance to tobacco dependence is then evaluated. While somewhat modest in size, the literature on chronic tolerance to nicotine in humans is reasonably consistent in showing clear evidence of tolerance to subjective mood effects but little or no tolerance to cardiovascular, performance or other nicotine effects, within the limitations inherent in most human research on tolerance. However, this research also indicates that chronic tolerance to nicotine is not closely associated with tobacco dependence: non-dependent and dependent smokers are equally tolerant; tolerance declines very little even years after quitting; and tolerance before quitting may have no relationship to clinical outcome of a cessation attempt. Recent research from the alcohol and substance abuse fields is consistent with the notion that tolerance has little clinical utility in determining dependence. These results question the relevance of nicotine tolerance to dependence and suggest that research into mechanisms of tolerance, while important for understanding biological adaptation, may not elucidate factors responsible for nicotine dependence. Future research should focus on whether dependence may be related to tolerance or to other, as yet unexamined, effects of nicotine, including conditioned tolerance effects, and on the possibility that tolerance may influence the early onset of dependence in teens even if apparently unrelated to maintenance of dependence in adult smokers.