Recent evidence indicates that neocortical electrocorticographic (ECoG) activation depends critically on cholinergic (ACh) inputs from the basal forebrain and serotonergic (5-hydroxytryptamine, 5-HT) inputs from the midbrain raphe to the neocortex. It appears that ACh and 5-HT block synchronized ECoG activity and induce cortical activation by a direct, local action in the neocortex that is not mediated by secondary systems. Concurrent blockade of cholinergic and serotonergic inputs to the cortex abolishes all ECoG activation, suggesting that: (a) together, ACh and 5-HT are essential for cortical activation to occur; and (b) other systems cannot maintain cortical activation in the absence of the cholinergic and serotonergic inputs. Nevertheless, additional neural systems (amygdala, locus coeruleus-noradrenaline (-NA), superior colliculus, orbitofrontal cortex, dopamine, histamine, glutamate) also modulate the ECoG and can produce cortical activation. In contrast to ACh and 5-HT, however, none of these systems are essential for the maintenance of cortical activation. Further, rather than producing activation via direct inputs to the neocortex, these systems appear to produce cortical activation by stimulating the cholinergic or serotonergic inputs to cortex. Thus, neocortical activation is maintained by multiple, parallel systems; cholinergic and serotonergic pathways are essential for activation and produce activation directly and locally in the neocortex, whereas additional pathways are not essential and contribute to activation indirectly by acting through these two direct activating inputs to the cortex.