The Drosophila model system has been used to study neurodegenerative diseases by expression of human disease genes in transgenic flies. A different approach is to isolate and characterize Drosophila mutants with progressive neurodegeneration to find novel genes required for brain integrity. Mammalian homologues of these genes might be the genetic basis for some of the various progressive neurodegeneration diseases in humans. Here we describe several such mutants. Some of them reveal degeneration in specific parts of the brain while others affect all brain regions. Cell death can occur through apoptosis or necrosis. In one case, mutant flies show abnormal behavior prior to obvious degeneration while most other mutants reveal such defects only in later stages. These mutants offer a new approach to study basic mechanisms of neurodegeneration and for developing fly models for human diseases.