Alzheimer disease (AD) is the most common form of senile dementia, and a cure is desperately needed. The amyloid-β 42 (Aβ42) has been suggested to play a central role in the pathogenesis of AD. However, the mechanism by which Aβ42 causes AD remains unclear. To understand the pathogenesis and to develop therapeutic avenues, it is crucial to generate animal models of Aβ42 toxicity in genetically tractable organisms. Drosophila is a well-established model system for which abundant genetic tools are available, and recently emerges as a model for human neurodegenerative diseases. We and others have established transgenic flies that express human Aβ42 in the nervous system. These Aβ42 flies developed age-dependent short-term memory impairment and neurodegeneration accompanied by Aβ42 deposits. Here we will summarize key features of transgenic Drosophila models of Aβ42 toxicity and a number of insights into disease mechanisms as well as therapeutic implications gained from these models.