The last 15 years of research in psychoneuroimmunology have been marked by a renewed interest in the mechanisms of inflammation and participation of the brain in these mechanisms. Peripheral proinflammatory cytokines produced by activated accessory immune cells act in the brain to trigger sickness, in the form of fever, pituitary-adrenal axis activation, and sickness behavior. Communication between the periphery and brain takes place via both neural and humoral pathways. Recognition of the role of local production of cytokines and their downstream messengers in the central nervous system opens important new vistas for understanding and treating non-specific neurovegetative and psychiatric symptoms of diseases. In this presidential address, I present the main methodological and conceptual developments that have allowed such progress.