Image-guided percutaneous transthoracic needle biopsy (PTNB) is a well-established and minimally invasive technique for evaluating pulmonary nodules. Implementation of a national lung screening program and increased use of chest computed tomography have contributed to the frequent identification of indeterminate pulmonary nodules that may require tissue sampling. The advent of biomarker-driven lung cancer therapy has led to increased use of repeat PTNB after diagnosis. Percutaneous insertion of markers for preoperative localization of small nodules can aid in minimally invasive surgery and radiation treatment planning. This article discusses PTNB, patient selection, and biopsy technique, including minimizing and managing complications.