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Donepezil is the leading compound for the treatment of Alzheimer's disease (AD) in more than 50 countries. As compared with other conventional acetylcholinesterase inhibitors (AChEIs), donepezil is a highly selective and reversible piperidine derivative with AChEI activity that exhibits the best pharmacological profile in terms of cognitive improvement, responders rate (40%-58%), dropout cases (5%-13%), and side-effects (6%-13%) in AD. Although donepezil represents a non cost-effective treatment, most studies convey that this drug can provide a modest benefit on cognition, behavior, and activities of the daily living in both moderate and severe AD, contributing to slow down disease progression and, to a lesser exetnt, to delay institutionalization. Patients with vascular dementia might also benefit from donepezil in a similar fashion to AD patients. Some potential effects of donepezil on the AD brain, leading to reduced cortico-hippocampal atrophy, include the following: AChE inhibition, enhancement of cholinergic neurotransmission and putative modulation of other neurotransmitter systems, protection against glutamate-induced excitotoxicity, activation of neurotrophic mechanisms, promotion of non-amyloidodgenic pathways for APP processing, and indirect effects on cerebrovascular function improving brain perfusion. Recent studies demonstrate that the therapeutic response in AD is genotype-specific. Donepezil is metabolized via CYP-related enzymes, especially CYP2D6, CYP3A4, and CYP1A2. Approximately, 15%-20% of the AD population may exhibit an abnormal metabolism of AChEIs; about 50% of this population cluster would show an ultrarapid metabolism, requiring higher doses of AChEIs to reach a therapeutic threshold, whereas the other 50% of the cluster would exhibit a poor metabolism, displaying potential adverse events at low doses. In AD patients treated with a multifactorial therapy, including donepezil, the best responders are the CYP2D6-related extensive (EM)(*1/*1, *1/*10) (57.47%) and intermediate metabolizers (IM)(*1/*3, *1/*5, *1/*6, *7/*10) (25.29%), and the worst responders are the poor (PM) (*4/*4)(9.20%) and ultra-rapid metabolizers (UM) (*1xN/*1) (8.04%). Pharmacogenetic and pharmacogenomic factors may account for 75%-85% of the therapeutic response in AD patients treated with donepezil and other AChEIs metabolized via enzymes of the CYP family. The implementation of pharmacogenetic protocols can optimize AD therapeutics.