Peroxisomes are ubiquitous and multifunctional cell organelles involved in diverse metabolic pathways, including a- and b-oxidation of fatty acids, the biosynthesis of docosahexaenoic acid and ether-phospholipids, and the metabolism of reactive oxygen species (ROS). In recent years, the peroxisome research field has been the subject of spectacular development. For example, growing evidence suggests that peroxisomes participate in redox-, lipid-, inflammatory-, and antiviral-signaling events. In addition, disturbances in peroxisome function have been linked to the development and progression of cellular aging and oxidative stress-related disease. However, there is still a large gap in our knowledge of how peroxisomes are integrated into subcellular signaling and communication networks. This study was intended to explore how cells cope with peroxisome-derived oxidative stress. First, we developed and validated a cell-based approach for studying the effects of KillerRed-induced oxidative insults. By employing this approach, we have provided novel solid evidence that excessive amounts of peroxisomal ROS trigger mitochondria-mediated cell death. In addition, we have demonstrated that the redox communication between peroxisomes and mitochondria involves complex signaling pathways that extend well beyond the simple diffusion of ROS from peroxisomes to mitochondria. Furthermore, we have obtained evidence that the presence of functional peroxisomes protects cells against the harmful effects of oxidative insults. Finally, we have found that Mdivi-1, an inhibitor of mitochondrial fission, also interferes with peroxisomal fission and renders cells more resistant to KillerRed-induced cell death. Taken together, these findings have important implications for our knowledge of how peroxisomes are integrated into cellular communication networks in health and disease. Indeed, they provide strong evidence that peroxisomes act as upstream initiators of mitochondrial ROS signaling pathways, and that mitochondria function as dynamic receivers, integrators, and transducers of peroxisomes-derived oxidative stress.