Stress is a stimulus or a succession of stimuli tending to disrupt the homeostasis of an organism. An organism is consisting of a multitude of cells that singly undergo the effects of external factors that disturb or upset their homeostatic regulation. Stimuli acting as potential stressors are numerous, and include physical agents (ionizing radiation), non-physiological oxygen levels (hypoxia, hyperoxia) and chemotherapeutics. Lastly, also senescence, a physiological process occurring in all organisms, can be considered as a potential stressor. The cell response to multiple oxidative stresses involves mitochondria, since these organelles represent the major source of Reactive Oxygen Species (ROS) that drive the occurrence of pathological conditions and ageing by activating specific signalling pathways. Nevertheless, under physiological conditions the cells are able to exert an antioxidant response which, controlling ROS/Reactive Nitrogen Species (RNS) homeostasis, is involved in mediating cell differentiation, proliferation and migration. Thus, this review focuses the attention to the role played by mitochondria in the physiological and non-physiological signalling responses of eukaryotic cells to some oxidative stresses, in order to identify potential therapeutic targets to counteract oxidative stress effects and mitochondrial-related pathologies.