Intrinsic signal optical imaging (ISI) is a high-resolution functional brain mapping technique that is being used to further our understanding of the neocortex and its interaction with drugs. Recent studies using combination ISI and in vivo pharmacology have advanced our insight into the actions of both acetylcholine and neurotrophins on inducing rapid and large-scale cortical plasticity. In particular, it appears that acetylcholine (ACh), nicotinic ACh receptors, nerve growth factor (NGF), and NGF receptors (TrkA and p75) are involved in an important feedback loop between the basal forebrain cholinergic system (BFCS) and the neocortex. Specifically, recent data suggest that NGF expressed in the cortex may act on multiple time scales on the BFCS: acutely to increase BFCS release of acetylcholine, intermediately to induce sprouting of BFCS axons, and long-term to change gene expression of BFCS neurons. In this article, advances in understanding the links in vivo between the BFCS, neocortex, nicotinic ACh receptors, and NGF are reviewed.