Objectives: To review the general toxicity profile of EGFR-targeted therapies and the management of the most common side effect, skin toxicity. Data Sources: Research articles. Conclusion: The most common side effect of anti-EGFR therapy is skin toxicity, which is generally mild to moderate, but may be severe in up to 18% of patients. Appearance of more severe rash has been correlated with better treatment outcomes. Skin toxicity is generally manageable with standard topical or systemic antibiotics and anti-inflammatory agents. Rash does not warrant treatment discontinuation; however, when using TKIs, the combination of rash and severe diarrhea may require treatment cessation. Implications for Nursing Practice: Patients and nurses need to be well informed about the expected side effects of anti-EGFR therapy and appropriate management techniques. Patient education prior to beginning therapy and proactive intervention at the first signs of skin toxicity are key to successful management. © 2006 Elsevier Inc. All rights reserved.