A pathway from the midbrain periaqueductal gray (PAG) through the ventromedial medulla (VMM) to the dorsal horn constitutes a putative endogenous nociceptive modulatory system. Yet activation of neurons in both PAG and VMM changes the responses of dorsal horn cells to nonnoxious stimuli and elicits motor and autonomic reactions that are not directly related to nociception. Activation of mu-opioid receptors in VMM and PAG also modifies processes in addition to nociceptive transmission. The descending projections of VMM neurons are not specific to nociception as VMM projects to the spinal superficial dorsal horn where thermoreceptors as well as nociceptors terminate. In addition, experiments with pseudorabies virus demonstrate multisynaptic pathways from VMM to sympathetic and parasympathetic target organs. VMM neurons respond to both noxious and unexpected innocuous stimuli of multiple modalities, and change their discharge during behaviors unrelated to pain such as micturition/continence and sleep/wake. In conclusion, all available evidence argues against the idea that PAG and VMM target nociception alone. Instead these brain stem sites may effect homeostatic adjustments made necessary by salient situations including but not limited to injury.