Abstract Conditional multireceptive (CMR) neurons respond in highly variable ways and exhibit extensive short-term and long-term experience-related changes that depend on the conditions being experienced by the organism, including external environmental factors, such as exigent events, and states of vigilance. CMR brain regions, which contain a large percentage of CMR neurons, are the major source for neuroplasticity in the brain. These CMR regions include the brainstem reticular formation (BRF), periaqueductal gray (PAG), hippocampus, amygdala, cerebellum, and cortical association areas, which exhibit this property to varying degrees. CMR regions are a major source of network nonlinearity, which leads to emergent properties at the neuronal network level of brain function. The extensive array of primary sensory and motor networks that provide inputs and receive outputs from these CMR regions allows the CMR regions to be major participants in network interactions that mediate many central nervous system (CNS) disorders. When the intact organism is experiencing resting (nonexigent) conditions, CMR neurons are commonly in a state of negative nonlinearity characterized by reduced or minimal neuronal responsiveness. However, under exigent conditions when the organism is experiencing a behaviorally important perturbation, such as pain or fear, the nonlinearity of CMR neurons and regions can actually reverse. Thus, under exigent conditions, CMR neurons can exhibit positive nonlinearity in which the output will be elevated, greatly exceeding a linear response. This positive nonlinear response provides a major mechanism for mediating the appearance of emergent properties of brain networks. CMR brain regions are postulated to be most susceptible to being recruited into networks that mediate CNS disorders as well as networks that are activated by stimulation therapies. Neurons in CMR regions are also greatly affected by CNS drugs, including depressant drugs, especially anesthetics, which greatly depress CMR neuronal responsiveness, even in small doses. CMR neurons are also extremely sensitive to CNS stimulants, such as gamma-aminobutyric acid A (GABAA) receptor antagonists, which can induce major positive nonlinear increases in responsiveness. The nature and degree of these pharmacological effects vary among different CMR regions. Positive nonlinearity of CMR regions can lead to network expansion and elevated sensorimotor integration, which are seen in the startle responses as well as in generalized seizures. Input repetition paradigms, such as seen in behavioral conditioning and seizure kindling, can lead to major responsiveness increases in CMR neurons. CMR regions are also known to interact with each other. For example, the BRF, PAG, and amygdala CMR regions are thought to interact in fear, mood disorders, and epilepsy in animal models and in human CNS disorders. Neurons in these brain regions are potentially critical targets for stimulation and/or drug therapy for these disorders.