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The clinical complexity, often attributed to the underlying genetics, includes several distinct syndromes (e.g., Barth syndrome; Pearson syndrome; Mitochondrial encephalomyopathy, lactic acidosis and stroke\u2010like episodes), some with overlapping symptoms. PMDs are highly heterogenous and affect multiple organs and tissues, prominently those with high energy demand such as muscle and neurologic tissues. Disease\u2010modifying therapies for PMDs approved by the United States Food and Drug Administration are few and disease\u2010specific, and treatment remains largely supportive in nature. The lack of robust biomarkers contributes to challenges associated with quantifying treatment responses in drug development. Recognizing this area of critical need, we sought to understand the landscape of molecular biomarkers that may inform treatment response, support clinical trials, and may be useful for regulatory decision\u2010making. In this review, we assess the extent of evidence and challenges for each biomarker. 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