Accurate diagnosis of muscle disease is dependent on a careful clinical examination followed by the appropriate laboratory investigations, which in a contemporary diagnostic center should also include ultrastructural investigations. As is the case in other tissues, the interpretation of the ultrastructural abnormalities observed in muscle must take into consideration several factors, in particular the small sample size, possible artifacts, and the nonspecificity of changes. Despite the fact that the majority of ultrastructural changes seen in muscle are not specific, electron microscopic examination still provides important and unique clues regarding patterns of change that characterize certain disease entities. Since this detailed ultrastructural information cannot at present be obtained by any other means, it is anticipated that electron microscopy will still play a vital role in the diagnosis of the nonneoplastic muscle diseases, well into the twenty-first century.