C. elegans has proven to be an excellent organism in which to model human neurodegenerative disease.^– The worm’s simple nervous system, lineage, and neural maps, easily scored movement phenotypes, and robust forward and reverse genetics make it optimal for studying age-dependent processes on a reasonable time scale. A popular approach has been the introduction of transgenes expressing GFP-tagged proteotoxic human proteins into neurons leading to visible aggregation or movement phenotypes.^,,,– In addition, the maintenance of proteostasis networks has been extensively studied using the power of worm genetics.^– These networks include genes involved in insulin-like signaling, the heat shock response, the response to hypoxia, and mTOR and AMPK pathways linked to aging. Another pathway with suggestive links to neurodegeneration is the O-GlcNAc cycling pathway, a nutrient-dependent post-translational modification known to be altered in brains from patients with Alzheimer disease.^– In this commentary, we summarize our recent findings showing that viable mutants of O-GlcNAc cycling in C. elegans dramatically alter the neurotoxicity of four distinct C. elegans models of neurodegenerative disease. Mutants in O-GlcNAc cycling alter the toxicity of mutant tau, polyglutamine expansion reporters, and amyloid β-peptide. The findings further suggest that O-GlcNAc cycling acts at many steps in the lifecycle of aggregation-prone targets. The C. elegans system is likely to continue to provide insights into this complex problem. The involvement of O-GlcNAc cycling in the maintenance of proteostasis raises the possibility of targeting the enzymes catalyzing this critical post-translational modification for therapeutic intervention.