Molecular chaperones are present in the various compartments of the cell and assist the folding of newly synthesized proteins. Compared to wild-type proteins, missense mutant proteins are generally synthesized in a normal fashion, but may be impaired in their folding. A broad array of diseases that are due to misfolding of mutant proteins may be labelled conformational diseases: aggregation diseases, such as Alzheimer disease; diseases caused by negative dominance from misfolded structural proteins, such as hypertrophic cardiomyopathy; and disorders where the misfolded protein is degraded by intracellular proteases. Many metabolic disorders belong to this last category, where the so-called protein quality control systems, comprising chaperones and proteases, attempt to eliminate folding intermediates or misfolded proteins. On the basis of in vitro experiments with a limited number of missense mutations identified in patients with phenylalanine hydroxylase and fatty acid oxidation deficiencies, we discuss the cellular fate of missense mutant proteins. We find that the balance between folding to functional conformers, retention (holding) and degradation of folding intermediates or misfolded proteins is dependent on the nature of the mutation and on the efficiency of the quality control. For example, low temperature may promote formation of functional conformers, while elevated temperature usually promotes retention and degradation. We conclude that disorders caused by many missense mutations are complex diseases in which the mutation itself is a necessary major primary component, but that its effect may be modified by cellular conditions and possibly by genetic variations in the quality control systems. We suggest that this new knowledge about cell handling may open new avenues of understanding of the cell pathology and treatment of patients with metabolic disorders.