The basal forebrain (BF) cholinergic system constitutes a heterogeneous cluster of large projection neurons that innervate the entire cortical mantle and amygdala. Cholinergic neuromodulation plays a critical role in regulating cognition and behavior, as well as maintenance of cellular homeostasis. Decades of postmortem histology research have demonstrated that the BF cholinergic neurons are selectively vulnerable to aging and age-related neuropathology in degenerative diseases such as Alzheimer's and Parkinson's diseases. Emerging evidence from in vivo neuroimaging research, which permits longitudinal tracking of at-risk individuals, indicates that cholinergic neurodegeneration might play an earlier and more pivotal role in these diseases than was previously appreciated. Despite these advances, our understanding of the organization and functions of the BF cholinergic system mostly derives from nonhuman animal research. In this chapter, we begin with a review of the topographical organization of the BF cholinergic system in rodent and nonhuman primate models. We then discuss basic and clinical neuroscience research in humans, which has started to translate and extend the nonhuman animal research using novel noninvasive neuroimaging techniques. We focus on converging evidence indicating that the selective vulnerability of cholinergic neurons in Alzheimer's and Parkinson's diseases is expressed along a rostral-caudal topography in the BF. We close with a discussion of why this topography of vulnerability in the BF may occur and why it is relevant to the clinician.