Reactive carbonyl species (RCS) are a class of reactive compounds that covalently react with nucleophilic substrates such as proteins. Reaction of RCS with proteins is involved in the onset and propagation of several oxidative-based diseases including atherosclerosis, diabetes and neurological disorders. RCS are efficiently detoxified by phase I and II metabolic pathways. More recently it has been found that histidine dipeptides, including carnosine and anserine, are involved in RCS detoxification by forming unreactive covalent adducts. Such a detoxification reaction was first demonstrated in vitro and then in vivo, in both rodents and humans, by detecting the conjugated metabolites between carnosine and the most reactive and abundant RCS, such as acrolein and hydroxynonenal. Furthermore, in animal models of metabolic syndrome and atherosclerosis, carnosine treatment induced a significant protective effect, which was associated with a reduction of RCS-modified proteins (ALEs and AGEs) and with the excretion of carnosine-RCS adducts. Such evidence, confirmed by different independent research groups, indicates that in physiopathological conditions characterized by oxidative damage, carnosine can act as an efficient RCS detoxification agent, reducing protein RCS modification and leading to a beneficial effect. Such studies prompted the discovery of carnosine derivatives resistant to carnosinase as a novel class of bioactive compounds.