Functional imaging has comprehensively demonstrated that pain involves a number of cortical regions that are often collectively referred to as the pain neuromatrix. This neuromatrix is assumed to be necessary to process the sensory, affective, and cognitive components of pain. Patients who report pain in the apparent absence of injury or disease may experience their symptoms because of dysfunction in one or more components of the pain neuromatrix. Two articles in this edition of Psychosomatic Medicine explore that possibility and provide evidence of altered neural connectivity and activation within components of the pain neuromatrix in patients with low back pain and irritable bowel syndrome. Questions remain as to how best to transition from describing the neural correlates of disease to understanding mechanisms and providing treatments.