Indeterminate pulmonary nodules (IPNs) are commonly encountered in interventional pulmonary practices. The challenge lies in how to proceed with diagnosis and management. Radiographic characteristics can help differentiate benign from malignant nodules. Several risk-stratification models have been developed based on the prevalence of cancer among different populations and can help determine the pretest probability of cancer (pCA). The American College of Chest Physicians (ACCP) and British Thoracic Society (BTS) have published guidelines incorporating the use of pCA to determine the next steps in diagnosis and treatment. Molecular biomarkers have been developed as additional diagnostic tools to determine risk of malignancy. Finally, obtaining a diagnosis requires a thoughtful approach to the technology available, the technique utilized, and appropriate patient selection to optimize diagnostic yield.