The prevalence of the insomnia syndrome and the effects of caffeine on sleep are in part genetically determined. Pharmacogenetic studies in humans demonstrate that functional polymorphisms of the genes encoding adenosine A2A receptors and dopamine transporters contribute to individual differences in impaired sleep quality by caffeine. The A2A receptor and dopamine transporter are preferentially expressed in the striatum. Together, these observations suggest that the striatum plays an important role in sleep-wake regulation. Individual caffeine sensitivity and A2A receptor genotype should be taken into account in the development of possible novel adenosine-based pharmacotherapies of sleep-wake disorders and neurodegenerative disorders such as Parkinson's disease. This may permit the prediction of individual drug effects and improve the reliability of clinical trials.