Transcriptional profiling has been used to identify gene expression patterns indicative of general medical illnesses such as atherosclerosis. However, whether these methods can identify common psychiatric disorders has not been established. To answer this question with respect to nicotine use, we used genome-wide expression profiling lymphoblast cell lines from six actively smoking Iowa Adoption Studies (IAS) subjects and nine "clean" control subjects, followed by real-time PCR (RT-PCR) of gene expression patterns in lymphoblast derived RNA from 94 subjects in the IAS. As compared to those from controls without a history of smoking (n = 9), the expression levels of 579 of 29,098 genes were significantly up-regulated and expression levels of 584 of 29,098 genes were significantly down-regulated in lymphoblast lines from currently smoking subjects (n = 6). RT-PCR confirmation of four select RNA levels confirmed the validity of the overall profile and revealed highly significant relationships between the expression of some of these transcripts and (1) major depression, (2) antisocial personality, (3) nicotine dependence, and (4) cannabis dependence. We conclude that the use of expression profiling may contribute significant insights into the biology of complex behavioral disorders.