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Reactive oxygen species (ROS) play a key role in systemic cell to cell signaling which is required for plant acclimation to different stresses, essential for the survival of plants. We recently developed a method to image real-time whole-plant accumulation of ROS and other systemic signals, and together with transcriptomic analysis and physiological measurements, we revealed the involvement of important signaling components in response to localized high light stress leading to systemic acquired acclimation (SAA) in Arabidopsis thaliana. The signal initiation and propagation maintenance are dependent on generation of ROS by RESPIRATORY BURST OXIDASE HOMOLOGS (RBOHs) in the apoplast and transport through the plasmodesmata, under the control of PLASMODESMATA LOCALIZED PROTEIN 1 (PDLP1) and PDLP5. Furthermore, we showed that phytochrome B acts in the same regulatory module as RBOHD and that it can regulate ROS production even if it is restricted to the cytosol. Additional proteins we discovered to function in the maintenance of the signal propagation, are aquaporin PLASMA INTRINSIC PROTEIN 2;1 (PIP2;1), that transport H2O2 across the plasma membrane and calcium channels including GLUTAMATE LIKE RECEPTORS 3.3 and 3.6 (GLR3.3 & GLR3.6), MECHANOSENSORS LIKE PROTEINS 2 and 3 (MSL2 & MSL3). Based on mutants and grafting experiments we identified the role of the ROS receptor HYDROGEN PEROXIDE INDUCED CALCIUM INCREASE 1 (HPCA1) in ROS cell to cell signal propagation, as well as the calcium signal propagation. We also reported that CALCINEURIN B-LIKE CALCIUM SENSOR 4 (CBL4), CBL4 INTERACTING PROTEIN KINASE 26 (CIPK26) and OPEN STOMATA 1 (OST1) are required for the cell-to-cell ROS signals. Altogether, screening more than 120 mutants, we shed light on the underling molecular mechanisms that coordinate the systemic cell to cell signals required for plant acclimation to stress. While most of our work focused on Arabidopsis, we were able to show the ROS auto propagation systemic signals are conserved in evolution and occur also in unicellular algae colonies, non-vascular plants and even mammalian cells. Thus, emphasizing the importance of the active process of cell-to-cell ROS signaling in communicating stress response signals between cells.