In this review, we first describe the mechanisms by which the epidermal growth factor receptor generates a Ca(2+) signal and, subsequently, we compile the available experimental evidence regarding the role that the Ca(2+)/calmodulin complex, formed after the rise in cytosolic free Ca(2+) concentration, exerts on the receptor. We focus not only on the indirect action that Ca(2+)/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 Ca(2+)/calmodulin with the receptor. We also describe several mechanistic models that could account for the Ca(2+)/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 Ca(2+) sensor by the epidermal growth factor receptor is highlighted.