In this review, we first describe the mechanisms by which the epidermal growth factor receptor generates a Ca²⁺ signal and, subsequently, we compile the available experimental evidence regarding the role that the Ca²⁺/calmodulin complex, formed after the rise in cytosolic free Ca²⁺ concentration, exerts on the receptor. We focus not only on the indirect action that Ca²⁺/calmodulin exerts on the epidermal growth factor receptor, as a result of the activation of distinct calmodulin‐dependent kinases, but also, and more extensively, on the direct interaction of Ca²⁺/calmodulin with the receptor. We also describe several mechanistic models that could account for the Ca²⁺/calmodulin‐mediated regulation of epidermal growth factor receptor activity. The control exerted by calmodulin on distinct epidermal growth factor receptor‐mediated cellular functions is also discussed. Finally, the phosphorylation of this Ca²⁺ sensor by the epidermal growth factor receptor is highlighted.