Any research pertaining to smoking or nicotine must demonstrate that its findings relate to changes in smoking or nicotine self-administration in order to be potentially relevant to understanding nicotine dependence or to treating smoking cessation. Nicotine alone, isolated from tobacco smoke, is self-administered by animals and humans. Pharmacological factors such as speed of dosing, dose amount, and pre-treatment with nicotinic antagonists clearly influence onset or rate of nicotine self-administration. However, environmental cues associated with nicotine intake can also substantially influence rate of self-administration and must be considered in the development of any treatment for smoking cessation. The specific acute subjective and behavioral effects of nicotine responsible for maintaining self-administration need to be identified, along with the minimum nicotine dose necessary for these effects. Individual differences in these effects, such as between men and women, also need to be examined. Findings in neuroscience and other areas of research need to be directly related to nicotine self-administration in order to clearly understand how they influence nicotine dependence. Overlooked by researchers is the influence of environmental factors, including social facilitation, on smoking or nicotine self-administration; these factors must be the primary cause of smoking relapse that occurs more than a week or so after a quit attempt. Laboratory-based findings must be extended to the natural environment to determine the degree to which they relate to smoking and nicotine reinforcement among smokers in the community (the population and venue for future treatment efforts).