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Recent advances in genome analysis and biochemical pathway mapping have advanced our understanding of how biological systems have evolved over time. Protein and DNA marker comparisons suggest that several of these systems are both ancient in origin but highly conserved into today's evolved species. However, remnants of some of the more ancient functions of these chemical systems can run in conflict with the functions that those same pathways serve in complex organisms and tissue systems today. Relevant to the present topic, nitric oxide (NO) and superoxide anion (O2•−), ancient cellular molecules in evolutionary terms, are recognized today as both necessary for the well-being and stable health of cells but also injurious to cells as elaborated in conjunction with the cellular stress response. Why the dichotomy? This question underlies one of the basic issues challenging researchers as well as practitioners in their approach to disease management. The fundamental proinflammatory response of the innate immune system of the host is needed for pathogen control but can be injurious to tissues from “collateral damage” from NO- and O2•−-derived reactive molecules capable of affecting protein function via post-translational chemical modification. This review highlights newer aspects of the biochemistry of the NO- and O2•−-mediated innate proinflammatory response and further show how protein and tissue damage via overproduction of reactive nitrogen and oxygen intermediary molecules such as peroxynitrite (ONOO−) might be targeted to specific epitopes of proteins. Changes in the regulation of metabolism in response to proinflammatory disease states are discussed for GH signal transduction and tissue specificity.