New advances in the treatment of non-small cell lung cancer (NSCLC) have afforded patients longer progression-free survival times, but these therapies are also associated with specific side effects that may not be seen with chemotherapy or radiotherapy. One class of agents includes the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), which have been shown to be efficacious in patients whose tumors harbor EGFR-activating mutations. Certain adverse effects, particularly rash and diarrhea, as well as mucositis/stomatitis, paronychia, ocular disorders, and interstitial lung disease, are seen with this class as a function of their mechanism of action. This review presents the suggested pathogenesis of these toxicities as well as specific management strategies to assist advanced practitioners in helping patients receive the full benefit of treatment with EGFR TKIs.