Since the identification of the cholinergic deficit, strategies aimed at enhancing cholinergic neurotransmission have dominated the field of pharmacology in Alzheimer's disease (AD). These strategies include increasing acetylcholine precursor availability, delaying synaptic degradation and stimulating muscarinic receptors. Although most clinical trials report mild symptomatic improvements in some patients, support for large-scale clinical use of cholinomimetics in AD is not yet available. This article presents the most representative clinical trials, discusses the limitations of the cholinergic strategies and suggests future directions in the treatment of AD.