The orexin neurohormones control a variety of important physiological processes by signaling through two related G protein-coupled receptors, including appetite and feeding, wakefulness and energy homeostasis. Pharmacological manipulation of orexin signaling is an important goal. Here we describe the isolation of orexin receptor ligands from a library of microarray-displayed peptoids via a novel two-color, cell-based screen. Functional analysis of derivatives of these "hits" resulted in the development of moderate potency, low molecular weight receptor antagonists. Moreover, further optimization efforts resulted in the fortuitous discovery of a compound that positively potentiates the activity of the receptor. This compound is the first small molecule reported to up-regulate orexin signaling.