Clinical development for primary mitochondrial diseases (PMDs) has spanned more than two decades, yet therapeutic success remains limited. In this Review, we provide a comprehensive, pharmacology-focused analysis of the PMD clinical trial landscape and identify key mechanistic and translational determinants underlying recent progress. A systematic survey of ClinicalTrials.gov covering January 2010 to April 2026 identified 159 registered studies across PMD subtypes after deduplication, including 110 interventional trials. Progress has been constrained by marked genetic and phenotypic heterogeneity, small and geographically dispersed patient populations, and the lack of validated pharmacodynamic and disease-specific endpoints. Consequently, several well-designed late-stage trials have yielded negative or inconclusive outcomes, and regulatory approvals have historically been scarce. Recent advances, however, indicate a shift in trajectory. Four therapies have achieved regulatory authorization, including idebenone for Leber hereditary optic neuropathy, taurine for MELAS, and recent FDA approvals of doxecitine and doxribtimine (Kygevvi) for thymidine kinase 2 deficiency and elamipretide (FORZINITY) for Barth syndrome. These successes share a convergent translational framework integrating mechanism-based pharmacology, genotype-driven patient selection, and biologically aligned endpoints. Clinical activity has also accelerated, with approximately half of PMD interventional trials initiated since 2020 and 50 studies currently active or recruiting. Emerging strategies include NAD⁺ augmentation, soluble guanylate cyclase stimulation, mTOR modulation, gene therapies, and heteroplasmy-targeting approaches. Collectively, these advances mark an emerging inflection point and suggest a path toward greater regulatory success in the coming decade.