Redox signaling plays a fundamental role in tissue physiological metabolism. A fine balance between reactive oxidizing species (ROS) generation and antioxidant levels allows either the cross talk between cells or the control of fundamental intracellular functions, such as cell-cell interactions, cell division, migration, and contraction. A deregulation of this balance, for example, leading to oxidative stress, has been implicated in many pathological conditions, including cardiovascular-, neuronal-, and immunological-related diseases, as well as in cancer. A key role of ROS generation has also been associated with a variety of cell death processes, including necrosis, apoptosis, and autophagy. More recently, the discovery that autophagy, formerly considered as a cell death program, mainly represents an important cytoprotection mechanism, led to a series of studies aimed at the comprehension of the role of ROS generation in regulating intracellular signals leading to the activation of survival mechanisms or triggering cell death. However, different cell types, for example, neuronal cells, muscle cells, lymphocytes, or epithelial cells, seem to display different redox sensitivities, different signaling pathways, and different defense mechanisms. In few words, as illustrated in detail in the present Forum, the future challenge on this matter will be represented by the comprehension of the histotype-associated or histotype-dependent intracellular mechanisms of ROS management.