In spite of affecting the life of millions of people, chronic traumatic brain injury (TBI) has not been hitherto treatable with effective pharmacological tools. This review gives a comprehensive summary of the theoretical data supporting the pharmacological manipulation of the cholinergic system in TBI, pointing out the most urgent targets for further studies. The published clinical evidence of cholinergic treatment in TBI is critically reviewed, with emphasis on modern available cholinergic agents. The lessons from these studies are converted to detailed suggestions for further clinical testing. In addition, the treating clinicians are provided with practical advice, based on personal experience of the cholinergic treatment in over 350 TBI patients. It is concluded that cholinergic agents offer several very promising potentials for the treatment of TBI. However, the final breakthrough requires further well-conducted studies and the potential caveats of the treatment have to be acknowledged.