Muscle biopsy remains a critical component in the evaluation of myopathies. Recent literature demonstrates that percutaneous biopsy instruments can effectively procure muscle tissue for analysis in clinical and research settings. We review issues of muscle biopsy technique and specimen processing in the context of available clinical methods for tissue analysis. A survey of recent literature illustrates contributions made by the histologic, histochemical, and ultrastructural aspects of muscle analysis to our understanding of the pathophysiologic mechanisms and clinical manifestations of selected inflammatory, mitochondrial, and infectious myopathies.