<p>Ferroptosis is a regulated form of cell death that depends on iron and is marked by lipid peroxidation and the inactivation of glutathione peroxidase 4. It has emerged as a pathway of broad relevance to cancer and neurodegenerative disease. Preclinical studies have identified potent ferroptosis inducers (System Xc⁻ and GPX4 inhibitors) and inhibitors (liproxstatin/ferrostatin derivatives, FSP1–CoQ10 activators) with promising therapeutic potential. However, clinical translation remains limited. Since dedicated therapeutics targeting ferroptosis are still in early development, current clinical evidence mainly comes from drug repurposing, approved drugs whose ferroptosis-modulating properties were discovered retrospectively after their initial approval. None of these completed trials used ferroptosis-specific pharmacodynamic data or prospectively tested ferroptosis as the primary therapeutic mechanism. Instead of just reclassifying these trials, this review introduces a four-category failure-mode framework, mechanism mismatch, biomarker absence, model-to-trial prediction, and target non-selective compound, to explain why preclinical signals of ferroptosis have yet to translate successfully. We conclude that progress depends on three developments: targeted modulators (purpose-developed or repurposed with confirmed engagement), proof-of-mechanism trials using ferroptosis-related endpoints, and patient selection aligned with precision medicine.</p>