Altered function of Cdk5 kinase is associated with many forms of neurodegenerative disease in humans. We show here that inactivating the Drosophila Cdk5 ortholog, by mutation of its activating subunit, p35, causes adult-onset neurodegeneration in the fly. In the mutants, a vacuolar neuropathology is observed in a specific structure of the central brain, the 'mushroom body', which is the seat of olfactory learning and memory. Analysis of cellular phenotypes in the mutant brains reveals some phenotypes that resemble natural aging in control flies, including an increase in apoptotic and necrotic cell death, axonal fragmentation, and accumulation of autophagosomes packed with crystalline-like depositions. Other phenotypes are unique to the mutants, notably age-dependent swellings of the proximal axon of mushroom body neurons. Many of these phenotypes are also characteristic of mammalian neurodegenerative disease, suggesting a close relationship between the mechanisms of Cdk5-associated neurodegeneration in fly and human. Together, these results identify the cellular processes that are unleashed in the absence of Cdk5 to initiate the neurodegenerative program, and they provide a model that can be used to determine what part each process plays in the progression to ultimate degeneration.