Myofibrillar myopathies (MFMs) are a group of heterogeneous muscle disorders morphologically defined by the presence of foci of dissolution of the myofibrils, accumulation of the products of myofibrillar degradation and ectopic expression of multiple proteins. MFMs represent the paradigm of conformational protein diseases of skeletal and cardiac muscles. Protein aggregation in MFMs is now considered to be the result of a failure of the extralysosomal proteolytic degradation system. Several factors including mutant proteins, aggresome formation and oxidative stress may compromise the ubiquitin-proteasome system, promoting the accumulation of potentially toxic protein aggregates within muscle cells.