Bilateral spontaneous pneumothorax is a rare occurrence in patients with both primary and metastatic lung cancer. Pneumothorax occurring as a complication of vascular endothelial growth factor receptor (VEGFR) inhibitor therapy has not been previously described in the medical literature. Sunitinib malate is a VEGFR inhibitor approved for the treatment of advanced renal cell carcinoma. We present a patient with metastatic renal cell carcinoma manifested as bilateral pulmonary nodules who developed a bilateral spontaneous pneumothorax 3 weeks after initiation of sunitinib therapy. We believe that sunitinib therapy resulted in necrosis of multiple pleural-based pulmonary nodules with central cavernization and ultimately rupture with bronchopleural fistula formation. Based on this experience, we advise that practitioners exercise caution when prescribing anti-VEGFR therapy in patients with pleural-based pulmonary metastases and recognize that the efficacy and toxicity of these agents may be closely linked.