The metal-catalyzed oxidation of histidine (His) to 2-oxo-histidine (2-oxo-His) represents an important pathway of protein oxidation in vivo and in vitro. In the pharmaceutical literature this pathway has received less attention. However, this fact may not necessarily represent reality as, in some cases, the analysis of His oxidation in proteins may be compromised by aggregation and precipitation of the target protein. For predicting the susceptibility of His residues in proteins it is important to understand in detail how protein sequence and conformation control the mechanisms of His oxidation to 2-oxo-His, reviewed in this paper.