There is broad agreement that randomized controlled double-blind trials (RCTs) do reveal only small effects of the cholinesterase inhibitors donepezil, rivastigmine and galantamine in the treatment of Alzheimer's disease (AD) (Perras et al., 2005; Cummings et al., 2002; Schneider, 2004). Furthermore, it is controversial whether the small effects shown in the RCTs are reliable or due to bias. In 2005 we published a systematic review of all RCTs on cholinesterase inhibitors which came to the conclusion that the scientific basis for a general recommendation of cholinesterase inhibitors in the treatment of AD is questionable because of the methodological shortcomings of the studies (Kaduszkiewicz et al., 2005). Following numerous debates on this topic at congresses and enriched through reviews of the U.K. National Institute for Health and Clinical Excellence (NICE, 2006) and the German Institute for Quality and Efficiency in Health Care (IQWiG, 2007), we will here present our actual view on this controversy. The main part of this article focuses on the methodology of cholinesterase inhibitor trials and on the interpretation of their results. We conclude by discussing briefly the three Cochrane reviews on cholinesterase inhibitors for AD.