Rapid and reliable identification of targetable driver mutations in patients with advanced stage lung cancer is essential. Adequate amount of tumor tissue biopsies (i.e., genomic biopsies) are required to successfully analyze the gene panel. In the present case, we performed three pleural fluid investigations, including transbronchial biopsy of the primary tumor, transesophageal endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of lymph node metastasis, and thoracoscopic biopsy of the pleural seeding sites. Among the three investigations, thoracoscopic biopsy alone successfully obtained a sufficient amount of tissue. Thus, it is important to determine the technique and site of biopsy, as multiple biopsies are not only burdensome to the patient, but also lead to significant delays in therapy induction.