Sleep is an important physiological state, but its function and regulation remain elusive. In Drosophila melanogaster, a useful model organism for studying sleep, forward genetic screens have identified important sleep-modulating genes and pathways; however, the results of such screens may be limited by developmental abnormalities or lethality associated with mutation of certain genes. To circumvent these limitations, we screened 1280 small molecules for effects on sleep in adult Drosophila. We used genetic and molecular approaches to elucidate the mechanisms by which two of these drugs altered sleep behavior. We found that administration of reserpine, a small molecule inhibitor of the vesicular monoamine transporter (VMAT) that repackages monoamines into presynaptic vesicles, resulted in an increase in sleep. We found that VMAT-null mutants, like reserpine-fed flies, have an increased sleep phenotype, as well as an increased arousal threshold and resistance to the effects of reserpine. However, although the VMAT mutants are consistently resistant to reserpine, other aspects of their sleep phenotype are dependent on genetic background. Thus, they may not have been detected in a classical forward genetic screen, further attesting to the utility of a small molecule screen. Mutations affecting single monoamine pathways did not affect reserpine sensitivity, suggesting that effects of VMAT/reserpine on sleep are mediated by multiple monoamines. We also studied the mode of action of caffeine, a common wake-promoting compound. Caffeine is thought to promote wake by inhibiting adenosine receptors, however previous work demonstrated that the wake-promoting effects of caffeine are independent of the adenosine receptor in the fly. We show that dopamine is required for the wake-promoting effect of caffeine in the fly, and that caffeine likely acts presynaptically to increase dopamine signaling. We identify a cluster of neurons, the paired anterior medial (PAM) cluster of dopaminergic neurons, which are essential for the caffeine response and which show increased activity following caffeine administration. Overall, we find that small molecule screens can be used effectively to identify regulators of adult behavior. The results of our screen and follow-up experiments demonstrate that presynaptic modulation of monoamine signaling may be a major source of sleep regulation.