Percutaneous computed tomography-guided transthoracic lung biopsy is an effective and minimally invasive procedure to achieve tissue diagnosis. Radiologists are key in appropriate referral for further workup, with percutaneous computed tomography-guided transthoracic lung biopsy performed by both thoracic and general interventionalists. Percutaneous computed tomography-guided transthoracic lung biopsy is increasingly performed for both diagnostic and research purposes, including molecular analysis. Multiple patient, lesion, and technique-related variables influence diagnostic accuracy and complication rates. A comprehensive understanding of these factors aids in procedure planning and may serve to maximize diagnostic yield while minimizing complications, even in the most challenging scenarios.