Effective treatment of cognitive impairments after traumatic brain injury (TBI) requires a clear understanding of the neuroanatomic and neurochemical bases of those impairments. Toward that end, this presentation will briefly review the structure and function of cerebral cholinergic systems in the brain and their role in cognition. The short- and long-term effects of TBI on cerebral cholinergic systems in the brain will be presented. That presentation will integrate findings from basic science (e.g., experimental injury studies) and clinical science (e.g., neuroimaging, electrophysiology, cerebrospinal fluid, and neuropathology) studies. Those findings and their translation to clinical studies, including multicenter randomized controlled trials, of medications for persistent cognitive impairments among persons with TBI then will be reviewed. Particular attention will given to the results from and clinical implications of three multicenter randomized clinical trials of acetylcholine-enhancing medications for persistent posttraumatic cognitive impairments. Future directions in this area of clinical neuroscience and lessons learned from studies performed to-date then will be discussed.