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Smoking is becoming increasingly concentrated in people with co-factors such as depression, attention deficit-hyperactivity disorder, anxiety disorders, and bulimia/bingeing. These behavioral or cognitive patterns may be adaptive or neutral in the conditions under which we evolved but maladaptive in environments requiring alertness for extended periods, where a fully mobilized fight-or-flight response is inappropriate, and where food availability makes lack of an "appestat" a liability. Such conditions are amenable to management by nicotine because of its ability to produce small but reliable adjustments in relevant cognitive and behavioral functions. Moreover, symptomatology may be unmasked or exacerbated by nicotine abstinence, persisting beyond the usual time-course for nicotine withdrawal, which may explain the particular attraction of smoking and the difficulty these individuals experience in quitting without necessarily requiring that they be more nicotine-dependent. The implications are: (1) a better understanding of the evolutionary psychobiology of smoking may promote development of tailored interventions for smokers with co-factors; (2) nicotine may have therapeutic applications for non-smokers with co-factors; (3) because smoking has a fairly high heritability index, and because of evidence of assortative mating, special prevention efforts targeting children of smokers with co-factors, as well as early identification of the co-factor itself, may be needed.