Whether studied from a structural or from a functional perspective, pain is an extraordinarily complex sensory modality. Because pain is an important means of warning an animal of dangerous circumstances, the mechanisms and pathways that subserve nociception are widespread and redundant. A distinct set of pain afferents with membrane receptors known as nociceptors transduces noxious stimulation and conveys this information to neurons in the dorsal horn of the spinal cord. The major central pathway responsible for transmitting the discriminative aspects of pain (location, intensity, and quality) differs from the mechanosensory pathway primarily in that the central axons of dorsal root ganglion cells synapse on second-order neurons in the dorsal horn; the axons of the second-order neurons then cross the midline in the spinal cord and ascend to thalamic nuclei that relay information to the somatosensory cortex of the postcentral gyrus. Additional pathways involving a number of centers in the brainstem, thalamus, and limbic forebrain mediate the affective and motivational responses to painful stimuli. Descending pathways interact with local circuits in the spinal cord to regulate the transmission of nociceptive signals to higher centers. Researchers have made tremendous progress in understanding pain in the last several decades, including transduction and sensitization of pain, pain-modulating neural circuits, network connectivity in chronic pain, and chronic pain modulation by glial cells and neuroinflammation. Much more progress seems likely, given the importance of the problem. Few patients are more distressed—or more difficult to treat—than those with chronic pain, a devastating by-product of the protective function of this vital sensory modality.