Several behavioral/psychological/psychiatric traits/disorders have been associated with increased initiation of smoking, nicotine dependence, and decreased cessation. Although much research has focused on psychiatric disorders, subclinical syndromes (e.g., minor depression and heavy drinking) probably influence smoking initiation and cessation more because they are so much more prevalent. In prospective studies, comorbidity predicts smoking and smoking predicts comorbidity. Preliminary evidence suggests several plausible mechanisms by which this two-way linkage could occur. In addition, other variables (e.g., genetics) could account for the comorbidity/smoking association. What we need to know: how strong and consistent are comorbidity/smoking associations? Is the association of smoking and comorbidity increasing over time? Are the hypothesized mechanisms for the association valid? Can treating comorbidity improve smoking cessation outcomes? Would applying the concept of comorbidity to psychosocial conditions (e.g., poverty) be helpful?