The major populations of cholinergic neurons in the brain include two "projection" systems, located in the pontine reticular formation and in the basal forebrain. These two complexes comprise, in part, the anatomical substrates for the "ascending reticular activating system" (ARAS). The pontine cholinergic system relays its rostral influences mainly through thalamic intralaminar nuclei, but it also connects to the basal forebrain and provides a minor innervation of cortex. The basal forebrain cholinergic complex (BFCC) projects directly to cortex and hippocampus, and has a minor connection with the thalamus. Recent data reveal that a parallel system of basal forebrain GABAergic projection neurons innervates cortex/hippocampus in a way that seems to complement the BFCC. Generally, the picture developed from more than 50 years of research is consistent with a "global" influence of these two ascending cholinergic projections on cortical and hippocampal regions. Seemingly, the BFCC acts in tandem or in parallel with the pontine cholinergic projection to activate the electro-encephalogram, increase cerebral blood flow, regulate sleep-wake cycling, and modulate cognitive function. There are quite a number and variety of human brain conditions, notably including Alzheimer's disease, in which degeneration of basal forebrain cholinergic neurons has been documented. Whether the corticopetal GABA system is affected by disease has not been established. Studies of degeneration of the pontine projection are limited, but the available data suggest that it is relatively preserved in Alzheimer's disease. Hypotheses of BFCC degeneration include growth factor deprivation, intracellular calcium dysfunction, amyloid excess, inflammation, and mitochondrial abnormalities/oxidative stress. But, despite considerable research conducted over several decades, the exact mechanisms underlying brain cholinergic vulnerability in human disease remain unclear.