Oxygen and derived ROIs became a threat for all organisms more than two billion years ago. Both prokaryotic and higher eukaryotic cells are able to alter their genetic programme in response to changes in the intracellular levels of reactive oxygen intermediates (ROIs). In bacteria and yeast, this response leads to the new synthesis of proteins that protect the induced cells from the consequences of oxidative damage, such as DNA strand breaks, lipid peroxidation and oxidative damage of proteins, thereby ensuring growth in a prooxidant environment. In higher eukaryotic cells, oxidative stress can be the consequence of reoxygenation of ischemic tissus or of exposure to environmental hazards. Intriguingly, multicellular organisms have also evolved cellular mechanisms to actively produce ROIs. In one case, the reactive compounds are needed as weapons against invading microorganisms. Granulocytes, neutrophils and macrophages have specialized in releasing of large amounts of H2O2 and superoxide. However, many other cell types can also inducibly produce ROIs but in amounts insufficient to threat microorganisms. There is increasing evidence that the small increases in ROI levels fulfil a role as second messengers. We propose that these pandemic pathogens have been conserved throughout evolution as universal pathogen messengers turning on genes with important functions in the immune response and cell proliferation. The higher eukaryotic transcription factor NF-kappa B will be described as a protein which is activated by ROIs under a great variety of pathogenic conditions and initiates the new expression of genes with important roles in inflammatory, immune and acute phase responses.