Alzheimer’s disease (AD), a main cause of dementia, is the most common neurodegenerative disease that is related to abnormal accumulation of the amyloid β (Aβ) protein. Despite decades of intensive research, the mechanisms underlying AD remain elusive, and the only available treatment remains symptomatic. Molecular understanding of the pathogenesis and progression of AD is necessary to develop disease-modifying treatment. Drosophila, as the most advanced genetic model, has been used to explore the molecular mechanisms of AD in the last few decades. Here, we introduce Drosophila AD models based on human Aβ and summarize the results of their genetic dissection. We also discuss the utility of functional genomics using the Drosophila system in the search for AD-associated molecular mechanisms in the post-genomic era.