The concept of somatization has a long history in psychosomatic medicine. What is missing, however, is an understanding of the way patients are able to perceive and represent somatic symptoms. Recent advances in psychoneuroimmunology offer new perspectives in this area. Proinflammatory cytokines produced by cells of the innate immune system in response to pathogen-associated molecular patterns and to endogenous danger signals act on the central nervous system via afferent and humoral pathways to trigger a brain cytokine system that organizes the sickness response in its subjective, behavioral, and metabolic components. There is evidence that prolonged activation of this system can precipitate the development of depressive disorders in vulnerable patients. The mechanisms that are responsible for the transition from sickness to depression involve alterations in tryptophan metabolism. There is also some indication that the brain cytokine system can become sensitized in response to non-immune stressors or to immune stressors occurring early in life. All these new findings have the potential to contribute to a renewed biopsychological approach to somatization and somatoform disorders.