Purpose of Review <p>This review explores the potential to target mitochondria as a therapeutic strategy in aggressive cancers, with a focus on Mesothelioma. We have compiled studies that investigate how mitochondrial aberrations across cancer and normal cells contribute to cancer pathogenesis. Additionally, we summarize strategies evaluating intrapleural therapy as a promising route for the administration of experimental and clinical stage therapies in mesothelioma.</p> Recent Findings <p>Emerging evidence suggests that mitochondrial dysfunction in various cancers contribute to metabolic reprogramming, supporting evasion from apoptosis, and resistance to therapy. Furthermore, targeting cancer cell metabolism has shown to be a promising strategy in making cells more vulnerable to apoptosis, often via the buildup of reactive oxygen species (ROS). Therapies such as RSO-021 induce tumor cell oxidative stress by inhibiting the mitochondrial antioxidant defense pathway comprising peroxiredoxin 3 (PRX3), causing a buildup of ROS and triggering apoptosis.</p> Summary <p>Changes in tumor cell metabolism, including mitochondrial activity, provide a therapeutic vulnerability that can be exploited by experimental, clinical stage, and approved therapies, especially in mesothelioma. New and emerging therapies targeting metabolism should be considered for intrapleural therapy for mesothelioma patients with malignant pleural effusions (MPE). In the future, these intrapleural administered mitochondria-targeting therapies could lead to improved survival outcomes for patients with mesothelioma.</p>