Pharmacologically, are smokers the same as non-smokers?

•Social context of smoking and personality traits describe subpopulations of smokers.•Smoking-related cues trigger activation of different neural networks.•Individual differences in smoking neurochemistry are influenced by genetic variants.•Experimental medicine models characterize differences between subpopulations.

Growing evidence suggests that there are subpopulations of daily smokers ranging from light infrequent users to heavy daily users. In the present review we will investigate whether these differences can be explained by factors such as social context, responsiveness to environmental cues, personality traits, neurochemical and pharmacogenetic differences. We will also assess how controlled abstinence and free choice smoking paradigms in a human laboratory setting may help identify and characterize these differences and what can be learned from these models to accurately predict clinical efficacy in the later phase testing of new chemical entities for the treatment of smoking dependence.