Most age-associated neurodegenerative disorders, including Alzheimer's, Parkinson's, Huntington's, and motoneuron disorders, are characterized by mislocalization, misfolding, and aggregation of disease-specific proteins in distinct neuronal cell populations and are therefore classified as proteopathies (Klaips et al., 2018). While diverse and partially redundant quality control mechanisms are in place to sustain proteostasis and cellular function, the accumulation of aggregation-prone proteins poses a constant burden on the proteostasis systems. With progressing cellular age, different quality control systems functionally decline, and long-lived cells such as neurons are particularly sensitive to misfolding and aggregation of proteotoxic proteins. Disease-associated oligomers and aggregates are directed to distinct protein quality control compartments, thereby compromising overall cellular fitness and survival. Proteopathies are commonly affected by disturbances of protein quality control subroutines, but also by impaired vesicle trafficking and critical mitochondrial damage. For dissecting pivotal interactions among different cellular pathways in the context of proteotoxicity, various cellular models have been established, including the baker's yeast Saccharomyces cerevisiae (Braun et al., 2010). S. cerevisiae is a genetically amenable unicellular eukaryotic model organism with a high degree of evolutionary conservation, in particular in respect to fundamental cellular processes such as protein quality control pathways, mitochondrial function and vesicle transport. Humanized yeast models based on the expression of human disease-associated aggregation-prone proteins have been successfully used to delineate molecular pathways underlying the loss of cellular fitness. In the Research Topic "Modeling Neurodegeneration in Yeast," we invited researchers to critically summarize recent developments and to present novel data using yeast to study human proteopathies.