The fundamental governing principles for the regulation of sleep are incompletely understood and neural substrates that, when activated, promote non-rapid eye movement (non-REM, NREM) sleep, also known as slow wave sleep, remain to be identified. The motivation to defy sleep and stay awake for a wide range of life-style choices is often accompanied by the use of psychoactive substances, most prominently caffeine. We have revealed that caffeine induces wakefulness by blocking adenosine A_2A receptors (A_2ARs) in the nucleus accumbens (NAc) (J Neurosci, doi: 10.1523/JNEUROSCI.6730-10.2011). Adenosine promotes sleep and for caffeine to be effective as an antagonist and cause arousal, excitatory A_2ARs must be tonically activated by endogenous adenosine. A_2ARs are highly expressed on neurons of the NAc that also express dopamine D₂ receptors (D₂Rs) and enkephalin (Enk), but the extent to which those A_2AR/D₂R/Enk-positive neurons in the NAc contribute to the regulation of sleep is not known. Optogenetic and pharmacogenetic activation of A_2AR neurons in the NAc induces robust NREM sleep. Selective deletion of A_2ARs in the NAc leads to increased nocturnal arousal and pharmacological activation of A_2ARs by the agonist CGS21680 increased NREM sleep in wild type, but not NAc-specific A_2AR knockout mice. Our observations provide direct evidence that adenosine and A_2AR neurons in the NAc are not only involved in promoting behavioral inactivity (inhibition of movement), but also play a major role in the regulation of sleep. These findings further suggest the intriguing possibility that the ventral striatum may be a key site through which sleep and wakefulness are regulated by behavioral processes and, by extension, that motivational state may be an important fundamental regulator of sleep and wake (Trends Neurosci, doi: 10.1016/j.tins.2012.07.001).