Views on drug therapy with acetylcholinesterase inhibitors of the cognitive symptoms of Alzheimer's disease are not uniform, varying from excitement at the possibility of significantly improving the personal and social burden of the disease to skeptical and nihilistic attitudes. Clinical practice from generous prescription to evidence-based guidelines and advising much stricter rules, mirror these attitudes. The epidemiological and clinical relevance of the issue requires understanding of the factors responsible for such discrepancies. Randomized clinical trials have only been able to address a few of the many variables that can affect the response to acetylcholinesterase inhibitors. The effect on behavioral symptoms, severe Alzheimer's dementia, and non-Alzheimer's forms of degenerative dementia need to be clarified as well as the modulating effect of frequently associated conditions such as cognitive changes due to physical diseases and cerebrovascular disease. The gap between evidence and clinical practice might be closed with appropriately designed observational studies rather than randomized clinical trials.