For our studies, the Brodsky laboratory utilizes a model eukaryotic organism, the yeast Saccharomyces cerevisiae. Yeast possess the same intracellular membrane organization and molecular chaperones as human cells but are amenable to rapid genetic analysis. Recent research in the Brodsky laboratory is currently directed toward understanding how molecular chaperones in the ER and the cytoplasm facilitate ERAD and protein folding in the cell. Both endogenous proteins and human proteins expressed heterologously in yeast are being examined as substrates for ERAD and chaperone-mediated folding, and data derived from our genetic studies are complemented by biochemical assays that recapitulate specific aspects of these processes. More recently, because of the connection between molecular chaperone function and human disease, we have begun to identify and screen for small molecules that affect chaperone activity, and to use proteomic and genomic attacks to identify additional components that facilitate ERAD.