The spinal dorsal horn is the first synapse in pain pathways and is a key target for regulation of nociceptive transmission by local and supraspinal mechanisms. Descending control of spinal nociception originates from multiple brain regions and plays a critical role in determining the experience of acute and chronic pain. Initially viewed as an "analgesia system," descending control is now understood to involve both inhibitory and facilitatory influences, depending on the context. The midline periaqueductal gray-rostral ventromedial medulla (PAG-RVM) system is a major source of descending control, with inhibitory effects on C-fiber mediated nociception and facilitatory effects on A-fiber mediated nociception. The RVM contains ON-cells and OFF-cells that differentially respond to higher brain structures, with ON-cells facilitating pain and OFF-cells inhibiting pain. The balance between these populations determines the overall level of pain processing. The caudal medulla also contributes to descending control, with the dorsal reticular nucleus (DRt) and ventrolateral medulla (VLM) playing roles in modulating nociception. These regions are involved in both inhibitory and facilitatory control, with the DRt showing pronociceptive effects and the VLM exerting tonic inhibition. The dynamic interplay between these systems is crucial for pain modulation, with changes in the balance between inhibitory and facilitatory control contributing to pathological pain states. Understanding the neural basis of descending control is essential for developing effective therapeutic strategies for pain management.The spinal dorsal horn is the first synapse in pain pathways and is a key target for regulation of nociceptive transmission by local and supraspinal mechanisms. Descending control of spinal nociception originates from multiple brain regions and plays a critical role in determining the experience of acute and chronic pain. Initially viewed as an "analgesia system," descending control is now understood to involve both inhibitory and facilitatory influences, depending on the context. The midline periaqueductal gray-rostral ventromedial medulla (PAG-RVM) system is a major source of descending control, with inhibitory effects on C-fiber mediated nociception and facilitatory effects on A-fiber mediated nociception. The RVM contains ON-cells and OFF-cells that differentially respond to higher brain structures, with ON-cells facilitating pain and OFF-cells inhibiting pain. The balance between these populations determines the overall level of pain processing. The caudal medulla also contributes to descending control, with the dorsal reticular nucleus (DRt) and ventrolateral medulla (VLM) playing roles in modulating nociception. These regions are involved in both inhibitory and facilitatory control, with the DRt showing pronociceptive effects and the VLM exerting tonic inhibition. The dynamic interplay between these systems is crucial for pain modulation, with changes in the balance between inhibitory and facilitatory control contributing to pathological pain states. Understanding the neural basis of descending control is essential for developing effective therapeutic strategies for pain management.