Cardinal manifestations of sickness include anorexia (lack of eating) and sleepiness/fatigue. The mechanism of this sick sleep involves signaling by cytokines acting on central nervous system neurons, but the mechanism downstream of the cytokines is unknown. We studied the mechanism of sick sleep using the laboratory animal Caenorhabditis elegans. When C. elegans is exposed to environmental conditions that cause sickness, including bacterial toxins, extreme heat, high osmolarity, or ultraviolet radiation, it will stop feeding (anorexia) and moving, and become less responsive to sensory stimulation. This sick behavior is abolished when a single interneuron called ALA (among a total of 302 neurons in the C. elegans nervous system) is removed (Hill et al, Cellular stress induces a protective sleep-like state in C. elegans, Curr. Biol. 24, p. 2399, 2014). Upon exposure to sick-inducing conditions, ALA is acted upon by the cytokine epidermal growth factor, which results in ALA depolarization and the release of neuropeptides encoded by the gene flp-13 (Nelson et al, FMRFamide-like FLP-13 neuropeptides promote quiescence following heat stress in Caenorhabditis elegans, Curr. Biol. 24, p. 2406, 2014). FLP-13 neuropeptides belong to a neuropeptide family characterized by an amidated Arginine-Phenylalanine (RFamide) motif at their C-termini. FLP-13 neuropeptides activate a seven transmembrane domain receptor, which is coupled to the inhibitory G-protein Gi/o (Trojanowski et al, Distinct mechanisms underlie quiescence during two Caenorhabditis elegans sleep like states, J. Neurosci. 35, p. 14571, 2015), resulting in a reduction of activity of wake promoting neurons. A peptidergic RFamide signaling mechanism functions also in sick sleep in Drosophila (Lenz et al, FMRFamide signaling promotes stress-induced sleep in Drosophila, Brain Behav. Immun. 47, 141, 2015), indicating that this mechanism is conserved across evolution. We propose that a similar mechanism functions in mammals to mediate anorexia and sleepiness during sickness.