Peripheral inflammatory processes elicit a number of CNS mediated sickness responses, including fever, fatigue, depression, anorexia, social avoidance, and increased stress hormone release. We examine the mechanisms by which peripheral immune signals are monitored by the brain to elicit these symptoms, and in particular how these signals can circumvent the blood-brain barrier. Using genetically modified mice with cell or tissue specific deletions of molecules involved in the inflammatory signaling cascade, or animals in which these molecules are selectively expressed in some cells/tissues, we study how peripherally released proinflammatory molecules activate blood-barrier cells, both in whole-body experiments and ex vivo in identified and isolated cells obtained by cell sorting techniques. Using fever as a primary physiological read-out, being a readily monitored, quantifiable and standardized response to inflammation, we examine how peripherally released cytokines activate intracellular pathways that trigger prostaglandin synthesis, and we examine how the interaction between pyrogenic and cryogenic signals shape the temperature response to the immune challenge. In a second associated line, we examine how peripheral inflammation as well as tumor generated messengers influence food intake and metabolism. Our work has implications for our understanding of the central processes involved in responding to acute and chronic peripheral inflammation and for finding novel treatments for the associated disease symptoms.