A schematic view of the proposed hypothesis on the evolutionary history of NO production and phytopathogenesis. Horizontal gene transfer (HGT) is represented by gray straight arrows. Denitrification, aerobic respiration, and photosynthesis reactions are represented by brown, blue, and pink curved arrows, respectively. Round shapes represent bacteria: thermophilic bacteria (TB, dark pink), thermophilic Cyanobacteria (TC, dark green), early mesophilic bacteria (EMB, pink) early mesophilic Cyanobacteria (EMC, olive green), mesophilic bacteria (MB, blue), and mesophilic Cyanobacteria (MC, green). A timeline is represented from early life conditions (ca 3.5 Gya), when a primitive atmosphere was essentially anoxic or microoxic (represented by the light pink sphere) to the development of an oxic atmosphere period, where facultative anaerobe and aerobe lifestyle is abundant (represented by the light blue sphere). Initially, HGT spread an ambivalent NO/oxygen reduction gene cluster (represented by the coincident blue and brown arrows in TB) in the early microbiota, which was subjected to speciation to oxygen reduction. Later, HGT of independently evolved aerobic respiration or denitrification gene clusters proceeded among thermophilic and early mesophilic bacteria, the latter arose in microoxic niches before the GOE. Note that these HGT events were probably widespread between intra- and inter-taxonomic groups of evolving thermophilic and mesophilic bacteria, and they are not all depicted. Atmospheric oxygen rose during GOE, due to cyanobacterial blooms, and led to the increase of aerobic mesophilic lifestyle. The oxygen boost inhibited nitric oxide reductase (NOR) in early microaerophilic and anaerobe denitrifiers and caused NO accumulation. NO toxicity caused “the first disease” in Cyanobacteria. During evolution both evolving Cyanobacteria and phytopathogens developed numerous defense and phytopathogenesis effectors, respectively. Establishment of the “disease” results from the balance between the effectors’ activity of both intervenient and the eventual NO surplus production by one of them is still a major determinant in the outcome of their interaction.