Independent discoveries in several laboratories suggest that the midbrain periaqueductal gray (PAG), the cell-dense region surrounding the midbrain aqueduct, contains a previously unsuspected degree of anatomical and functional organization. This organization takes the form of longitudinal columns of afferent inputs, output neurons and intrinsic interneurons. Recent evidence suggests: that the important functions that are classically associated with the PAG--defensive reactions, analgesia and autonomic regulation--are integrated by overlapping longitudinal columns of neurons; and that different classes of threatening or nociceptive stimuli trigger distinct co-ordinated patterns of skeletal, autonomic and antinociceptive adjustments by selectively targeting specific PAG columnar circuits. These findings call for a fundamental revision in our concept of the organization of the PAG, and a recognition of the special roles played by different longitudinal PAG columns in co-ordinating distinct strategies for coping with different types of stress, threat and pain.