Objective This video depicts thoracoscopic left upper lobectomy of lung adenocarcinoma after targeted therapy with discussion of how to approach variation in vascular anatomy and bleeding/air leak challenges in a minimally invasive setting. Summary A 59-year-old male with excellent functional status and noncontributory history presented for treatment of oligometastatic lung adenocarcinoma with EGFR mutation. Prior bilateral craniotomy and gamma knife radiation were utilized to resect two brain metastases. The primary lung tumor (3.1 cm) was in the lingula of the left lung. Interdisciplinary workup suggested treatment with targeted therapy and subsequent resection. Following 75 days of osimertinib, the tumor shrank to 2.3 cm and surgery proceeded. During surgery, this patient was found to have 8 branches of the pulmonary artery requiring that we significantly adjust operative progression. Additionally, lung tissue was easily damaged. Literature has shown a plausible link between osimertinib and increased bleeding. Moreover, persistent chest tube air leak has been reported with use of targeted therapy. Likewise, we suspect that the lung friability is partly due to osimertinib used prior to surgery and that this fragility played a significant factor in perioperative arterial/air leaks. Hemostatic agents and comprehensive surgical repair were required to control intraoperative bleeding and air leaks. Persistent post-operative air leak required discharge with a chest tube and drain valve. Conclusions Lung resection following targeted therapy can present challenges related to lung fragility. We demonstrate a VATS approach to successful lobectomy in the setting of preoperative targeted therapy, complex arterial anatomy, tissue friability, and air leak.