Epidermal growth factor receptors (EGFRs) play an important role in the development of the skin and up-regulation of these receptors is associated with many cancer-related processes, such as inhibition of apoptosis and uncontrolled cell proliferation. Accordingly, treatment of metastatic colorectal cancer with EGFR inhibitors may lead to adverse cutaneous effects that can decrease the patient's quality of life and could possibly lead to reduced, interrupted, or discontinued therapy. Effective management of these adverse effects may lessen the chance of suboptimal therapy and requires an understanding of the underlying pathophysiology, as well as knowledge of useful strategies for alleviating these effects.