Dermatologic events are considered the most relevant elements of the toxicity profile of epidermal growth factor receptor (EGFR) inhibitors. However, some nondermatologic adverse events can also be common. Although these toxicities are rarely severe, they may have fatal outcomes if not managed appropriately. For example, gefitinib (Iressa) and erlotinib (Tarceva) (and more rarely, cetuximab [Erbitux]) are associated with a risk of interstitial lung disease, while the administration of cetuximab may be associated with infusion reactions. Preparedness to assess patients at risk and to manage symptoms promptly and effectively can greatly reduce any potential risks. As a result, anti-EGFR therapies are generally well tolerated. As anti-EGFR agents are integrated into standard regimens or combined with novel treatments, familiarity with their safety profiles will become increasingly important. This article reviews the key nondermatologic adverse events associated with cetuximab, gefitinib, and erlotinib, and summarizes the most important management recommendations.