Arginine (Arg) has long been known to be a major regulator of immunity via its metabolic and physiological functions. In the 1950s, it was classified as a non-essential amino acid by Rose since Arg could be synthesized at the whole body level, mainly in the kidneys, after the conversion of intestinal citrulline (Cit) via argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL). But things changed when Barbul et al. (Surg Forum 28:101–103, 1977) observed, surprisingly, that Arg was an immunomodulator via a thymic effect. At the same time, they observed that Arg could be essential in several situations, like growth or sepsis. Finally in the 1990s, Albina et al. (J Immunol 147:144–148, 1991) demonstrated that macrophages were able to produce nitric oxide (NO). These pioneering observations opened a new field of research focused on the regulation of macrophage functions by Arg.