Protein aggregation is frequently associated with disease and dysfunction, but is also vital to many aspects of normal biology, from meiosis to memory. Unfortunately, protein aggregates are notoriously difficult to compare and quantify. We have developed a synthetic sensor for protein aggregation in yeast by coupling the solubility of a given protein to a fluorescent or enzymatic reporter. This modular platform is amenable to quantitative, high throughput screening and selection, or can be used to measure individual live cells with microscopy. We applied the tool first to study yeast prions, which are heritable, self-templating protein conformations that confer different phenotypes depending on their conformational state. Screening a pool of random mutations in prion genes, we identified dominant mutations in yeast prions that solubilize and cure the endogenous, wild type prion aggregate. One of these mutations is already harbored by rare, wild strains of yeast. We predict that this strain would be immune to a yeast prion and would cure the prions of its mating partners. We then conducted screens of environmental stresses and a natural product library to uncover drugs and conditions that affect prion switching. We identified a number of drugs and conditions that yeast may encounter in their natural habitat and are active in switching their prion state. Encountering these factors would cause a heritable prion switch that would be ‘remembered’ by the population for generations to come, significantly altering their phenotype. Our technology is also applicable to the analysis of non-prion aggregates. We have utilized the technique to measure sequestration of endogenous cellular proteins by aggregation-prone human disease proteins in vivo. We used this to learn about the sequence elements that influence the interaction of the disease aggregate with endogenous proteins. This technique unlocks previously-inaccessible questions in the investigation of protein aggregation.