Tryptophan (TRP), an essential amino acid in mammals, is involved in several physiological processes including neuronal function, immunity, and gut homeostasis. In humans, TRP is metabolized via the kynurenine and serotonin pathways, leading to the generation of biologically active compounds, such as serotonin, melatonin and niacin. In addition to endogenous TRP metabolism, resident gut microbiota also contributes to the production of specific TRP metabolites and indirectly influences host physiology. The variety of physiologic functions regulated by TRP reflects the complex pattern of diseases associated with altered homeostasis. Indeed, an imbalance in the synthesis of TRP metabolites has been associated with pathophysiologic mechanisms occurring in neurologic and psychiatric disorders, in chronic immune activation and in the immune escape of cancer. In this chapter, the role of TRP metabolism in health and disease is presented. Disorders involving the central nervous system, malignancy, inflammatory bowel and cardiovascular disease are discussed.