Improvements to the diagnosis and treatment of Parkinson disease (PD) are dependent upon the identification and molecular understanding of modifiers of neuronal degeneration. Here, we describe the use of multifactorial functional analyses to exploit the experimental attributes of the nematode, Caenorhabditis elegans, to accelerate the translational path toward identification and characterization of modifiers of dopaminergic neurogeneration. C. elegans is ideal for both screening and target validation of potential modifiers. Specific assays discussed in this technical overview include in vivo analyses using whole, intact, and living nematodes with readouts for age-dependent α-synuclein-proteotoxicity and 6-hydroxydopamine-induced neurodegeneration in dopamine (DA) neurons. These methods provide an integrated approach to target characterization and functional validation in C. elegans that allow researchers to prioritize lead candidates for translation toward mammalian systems. © 2011 Springer Science+Business Media, LLC.