The Multiple Determinants of Pain The neuromatrix theory of pain proposes that the neuro-signature for pain experience is determined by the synaptic architecture of the neuromatrix, which is produced by genetic and sensory influences. The neuro-signature pattern is also modulated by sensory inputs and by cognitive events, such as psychological stress. It may also occur because stressors, physical as well as psychological, act on stress-regulation systems, which may produce lesions of muscle, bone, and nerve tissue, thereby contributing to the neuro-signature patterns that give rise to chronic pain. In short, the neuromatrix, as a result of homeostasis regulation patterns that have failed, produces the destructive conditions that may give rise to many of the chronic pains that so far have been resistant to treatments developed primarily to manage pains that are triggered by sensory inputs. The stress regulation system, with its complex, delicately balanced interactions, is an integral part of the multiple contributions that give rise to chronic pain. The neuromatrix theory guides us away from the Cartesian concept of pain as a sensation produced by injury, inflammation, or other tissue pathology and toward the concept of pain as a multi-dimensional experience produced by multiple influences. These influences range from the existing synaptic architecture of the neuromatrix—which is determined by genetic and sensory factors—to influences from within the body and from other areas in the brain. Genetic influences on synaptic architecture may determine, or predispose toward, the development of chronic pain syndromes. Figure 1 summarizes the factors that contribute to the output pattern from the neuromatrix that produce the sensory, affective, and cognitive dimensions of pain experience and behavior. We have traveled a long way from the psychophysical concept that seeks a simple one-to-one relationship between injury and pain. We now have a theoretical framework in which a genetically determined template for the body-self is modulated by the powerful stress system and the cognitive functions of the brain, in addition to the traditional sensory inputs. The neuromatrix theory of pain—which places genetic contributions and the neural-hormonal mechanisms of stress on a level of equal importance with the neural mechanisms of sensory transmission—has important implications for research and therapy. The expansion of the field of pain to include endocrinology and immunology may lead to insights and new research strategies that will reveal the underlying mechanisms of chronic pain and give rise to new therapies to relieve the tragedy of unrelenting suffering.