Desmin, the muscle-specific memberof the intermediate filament (IF) family, is one of the earliest knownmyogenicmarkers in both skeletal muscleand heart. Its expression precedes that of all knownmuscle proteins including the membersof the MyoDfamily of myogenic helix-loop-helix (mHLH) regulators with the exception of myf5. In mature striated muscle, desmin IFs surround the Z-discs, interlink them together and integrate the contractile apparatus with the sarcolemmaandthe nucleus. In vitro studies using both antisense RNAand homologous recombination techniques in embryonic stem (ES) cells demonstrated that desmin plays a crucial role during myogenesis, as inhibition of desmin expression blocked myoblast fusion and myotubeformation. Both in C2C12cells and differentiating embryoid bodies, the absence of desmin interferes with the normal myogenic program, as manifested by the inhibition of the mHLHtranscription regulators. Toinvestigate the function of desmin in all muscle types in vivo, wegenerated desminnull mice through homologousrecombination. Surprisingly, a considerable numberof these mice are viable and fertile, potentially due to compensation by vimentin, nestin or synemin. However, desmin null mice demonstrate a multisystem disorder involving cardiac, skeletal and smooth muscle, beginning early in their postnatal life. Histological and electron microscopic analysis in both heart and skeletal muscle tissues reveals severe disruption of muscle architecture and degeneration. Structural abnormalities include loss of lateral alignment of myofibrils, perturbation of myofibril anchorage to the sarcolemma, abnormal mitochondrial numberand organization, and loss of nuclear shape and positioning. Loosecell adhesion and increased intercellular space are prominent defects. Theconsequences of these abnormalities are most severe in the heart, whichexhibits progressive degeneration and necrosis of the myocardiumaccompaniedby extensive calcification. Abnormalities of smoothmuscle included hypoplasia and degeneration. There is a direct correlation between severity of damageand muscle usage, possibly due to increased susceptibility to normal mechanical damageand/or to repair deficiency in the absence of desmin. In conclusion, the studies so far have demonstrated that though desmin is absolutely necessary for muscle differentiation in vitro, muscle development can take place in vivo in the absence of this intermediate filament protein. However, desminseemsto play an essential role in the maintenance of myofibril, myofiber and wholemuscletissue structural and functional integrity.