Abstract: Tight regulation of iron is a paramount defense mechanism to the human organism, since disorders of iron metabolism such as iron overload can be deadly. In addition, sophisticated molecular uptake and transport systems have resulted from the arms race between bacteria and humans for iron. Invading microorganisms produce siderophores to scavenge iron in the host and remove the metal from iron-binding proteins. In response, the innate immune protein siderocalin can intercept the ferric complexes formed with some siderophores. Thus, pathogenic bacteria must produce additional stealth siderophores to evade the innate immune system. The present study aims at understanding processes involved in iron acquisition and regulation in both micro- and human organisms. The coordination chemistry of enterobactin, one of the most powerful siderophores, has been thoroughly investigated. The ferric complex of enterobactin undergoes a coordination shift from catecholate to salicylate geometry upon protonation, which may facilitate iron release through acidic compartments once in the microbial cell. Such a structural change was characterized and confirmed by thermodynamic, spectroscopic (EXAFS and NMR) and electrochemical analysis. Binding of the innate immune protein siderocalin to ferric-enterobactin relies on hybrid electrostatic/cation-π interactions. These interactions were examined using fluorescence and UV-vis spectroscopies, which elucidated the role of each amino acid contained in the protein binding site, and of the complex protonation state, as recognition is lost upon acidification. Fluorescence spectroscopy was also used to probe the specificity of siderocalin recognition. Binding studies performed with natural siderophores including salmochelins isolated from Salmonella species, bacillibactin and petrobactin produced by Bacillus species such as Bacillus anthracis, as well as with a variety of synthetic analogs, gave prominence to the molecular strategies used by pathogenic bacteria to evade siderocalin. The study of siderophores is also relevant to the treatment of non-infectious diseases, since siderophore mimics are the most promising chelating agents for therapeutic treatments of iron-overload. New hexadentate ligands incorporating hydroxypyridinone and terephthalamide iron-binding units have been synthesized. These compounds form stable ferric complexes, characterized thermodynamically and electrochemically. Two ligands emerged as promising therapeutic iron chelators from lipophilicity and kinetic rates measurements, along with in vivo stability and efficacy evaluations.