Alzheimer's disease is a neurodegenerative disease characterized by senile plaques, neurofibrillary tangles, synaptic loss, neuronal death and cholinergic deficits, causing cognitive, behavioral and psychological deficits, as well as a functional impairment that results in serious caregiver distress and a great economic burden worldwide. High hopes rose with the development of symptomatic treatments,resulting from randomized controlled trials using cholinergic enhancers or cholinesterase inhibitors, such as donepezil, galantamine and rivastigmine. When memantine, an NMDA antagonist,was approved and the first phase III antiamyloid immunization was launched, many clinicians eagerly anticipated the first disease-modifying drugs in their daily practice. For the treatment of behavioral and psychological symptoms of dementia (BPSD), atypical antipsychotics and new-generation antidepressants also seemed to offer great promises, mainly because of their good tolerance and side effect profiles. Hopes, however, were followed by desillusions: subsequent studies demonstrated that cholinesterase inhibitors and memantine had only modest and short-lived effects on cognition and BPSD, and the effect of antipsychotics on BPSD appeared questionable. Disease-modifying drugs such as antiamyloid immunization or amyloid clearance medication had to be abandoned for safety reasons or absence of efficacy. Although the early treatment of vascular risk factors is increasingly recognized in Alzheimer's disease prevention because of their implication in the amyloid cascade, randomized controlled trials have yielded largely negative results. Therefore,pharmacological as well as fundamental research that better underpins the complex pathophysiology of this devastating disease constitutes one of the biggest challenges of the 21st century.