Previous evidence has shown that prostaglandins play a key role in the development of sickness behavior observed during inflammatory states. In particular, prostaglandin E2 (PGE2) is produced in the brain by a variety of inflammatory signals such as endotoxins or cytokines. Its injection has been also shown to induce symptoms of sickness behavior. The role of cyclooxygenase enzymes (COX), the rate-limiting enzymes converting arachidonic acid into prostaglandins, in sickness behavior has been extensively studied, and it has been demonstrated that strategies aiming at inhibiting these enzymes limit anorexia, body weight loss and fever in animals with inflammatory diseases. However, inhibiting COX activity may lead to negative gastric or cardiovascular effects, since COX enzymes play a role in the synthesis of others prostanoids with various and sometimes contrasting properties. Recently, prostaglandin E synthases (PGES), which specifically catalyze the final step of PGE2 biosynthesis, were characterized. Among these enzymes, the microsomal prostaglandin E synthase-1 (mPGES-1) was of a particular interest since it was shown to be up-regulated by inflammatory signals in a variety of cell types. Moreover, mPGES-1 was shown to be crucial for correct immune-to-brain communication and induction of fever and anorexia by pro-inflammatory agents. This review takes stock of previous knowledge and recent advances in understanding the role of prostaglandins and of their specific synthesizing enzymes in the molecular mechanisms underlying sickness behavior. The review concludes with a short summary of key questions that remain to be addressed and points out therapeutic developments in this research field.