Lung cancer is a lethal disease with high mortality, and treatment modality varies with type of tumor and stage of the disease. Targeted molecular therapies have been developed for patients with advanced non-small cell lung cancer. The presence of epidermal growth factor receptor (EGFR) mutation qualifies the patient for EGFR-TKI (tyrosine kinase inhibitor) therapy such as erlotinib, which is not without risk. We report an interesting case of duodenal perforation secondary to erlotinib therapy. This is the second reported case of bowel perforation after erlotinib therapy in a patient with advanced non-small cell lung cancer.