L-arginine:glycine amidinotransferase is the first enzyme in creatine biosynthesis. The activity of this enzyme is tightly regulated in vivo to maintain normal creatine metabolism. Since the enzyme activity appears to be compromised in medical conditions, such as heart failure, chronic kidney disease, or stroke, it is a tempting target for upregulation in conditions with low creatine levels. This paper provides an update on specific nutraceuticals that are reported to modulate L-arginine:glycine amidinotransferase activity and discusses possible implications of targeting this enzyme in experimental and clinical nutrition. Several promising nutritional agents (e.g. creatine, norvaline, cysteine) have been identified that modulate L-arginine:glycine amidinotransferase activity and the resultant cellular bioenergetics. However, most studies lack a apparent mechanism(s) of action and clinical applicability, with only one compound identified so far for much-needed L-arginine:glycine amidinotransferase upregulation.