Molecular chaperones are master regulators of protein folding quality control, and it is widely accepted that these functions are aberrantly exploited in human tumors. What has also emerged in recent years is that chaperone control of protein folding does not occur randomly in cells, but is spatially compartmentalized in subcellular organelles and specialized microenvironments. Fresh experimental evidence has now uncovered a role for mitochondrial localized chaperones to oversee the protein folding environment within the organelle, selectively in tumor cells. Perturbation of this compartmentalized chaperone network triggers an array of compensatory responses that aims at restoring homeostasis, while also providing novel opportunities for rational cancer therapy.