Recently, several reports appeared which described auto‐phosphorylation of NDP kinase on residues different from the active‐site histidine. Based on these findings conclusions were drawn with respect to a regulation of enzyme activity and to a possible role as a metastasis suppressor. In this paper we show that although non‐histidine autophosphorylation occurs on NDP kinases from mammals, lower eukaryotes and bacteria, less than 0.2% of the subunits are phosphorylated. Using site‐directed mutagenesis, we show that the active site histidine is essential for non‐histidine autophosphorylation. The low stoichiometry of phosphate incorporation excludes a role of autophosphorylation in regulating overall enzyme activity.