Under normal growth conditions, tumor-suppressor proteins and oncogenes play key roles in the tight regulation of cell division (1). Tumorigenesis often arises from mutations that interfere with the appropriate function of these regulatory proteins. Tumor-causing mutations may result in either an alteration of the catalytic activity of the protein, loss of a binding site for a partner or effector protein, or an alteration of the native folded conformation. There are a growing number of examples in which protein misfolding is associated with tumorigenesis. In some cases, misfolded tumor supressors are simply inactive and lead to cancer as a result of a loss-of-function phenotype, as in the case of tumor-suppressor proteins VHL and NF2. Alternatively, the mutated proteins may adopt an aberrant conformation that is regulated differently than the wild-type protein. Such mutations may lead to a dominant-negative inactivation of the wild-type tumor suppressor, as in the case of p53 and WT1, or to constitutive activation of an oncogenic protein, as in the case of the Src family kinases. Here we review a number of examples that illustrate how alterations in the folding of tumor-suppressor proteins or oncogenes lead to carcinogenesis. Most of the cases also involve altered interactions of these proteins with the components of the cellular folding machinery. Eukaryotic molecular chaperones such as TRiC/CCT, Hsp70, and Hsp90 play important roles in both assisting protein folding and in quality-control processes that recognize and target misfolded proteins for degradation by the Ubiquitin-26S Proteasome pathway (2,3).