Animals respond to illness with a conserved behavioral response including anorexia, fever, fatigue and sleep. The current biological framework for explaining this behavioral response is that immune cells send inflammatory signals to the brain to trigger the sickness behavior program. The field does not currently understand how the brain responds to these inflammatory signals, and what neural signaling changes cause this dramatic shift in behavior. Here, I review our understanding of neural mechanisms of sickness sleep and fatigue, covering research in invertebrate model organisms as well as mammals. I describe my experimental work to identify neural and genetic signaling mechanisms controlling sleep during viral infection in the nematode Caenorhabditis elegans. I discuss my attempts to develop a preclinical model of cancer related fatigue, using radiation therapy in mice. Finally, I describe my experiments on fatigue controlled by RFamide neuropeptide signaling, a conserved signal that controls sleep in worms, flies and fish. I provide evidence that NPVF – a member of the RFamide family - controls sickness sleep in mammals. Together, my work shows that mechanisms driving fatigue and sickness behavior are phylogenetically conserved. I have shown that the neural mechanisms underlying sleep during health and sickness in worms are distinct, indicating that there may be sickness-sleep specific neural circuits in other organisms as well.