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Proteinopathies are degenerative diseases in which specific proteins adopt deleterious conformations, leading to the dysfunction and demise of distinct cell types. They comprise some of the most significant diseases of aging-from Alzheimer's disease to Parkinson's disease to type 2 diabetes-for which not a single disease-modifying or preventative strategy exists. Here, we survey approaches in tractable cellular and organismal models that bring us toward a more complete understanding of the molecular consequences of protein misfolding. These include proteome-scale profiling of genetic modifiers, as well as transcriptional and proteome changes. We describe assays that can capture protein interactomes in situ and distinct protein conformational states. A picture of cellular drivers and responders to proteotoxicity emerges from this work, distinguishing general alterations of proteostasis from cellular events that are deeply tied to the intrinsic function of the misfolding protein. These distinctions have consequences for the understanding and treatment of proteinopathies.