The 2010's saw demonstration of the power of lung cancer screening to reduce mortality. However, with implementation of lung cancer screening comes the challenge of diagnosing millions of lung nodules every year. When compared to other cancers with widespread screening strategies (breast, colorectal, cervical, prostate, and skin), obtaining a lung nodule tissue biopsy to confirm a positive screening test remains associated with higher morbidity and cost. Therefore, non-invasive diagnostic biomarkers may have a unique opportunity in lung cancer to greatly improve the management of patients at risk. This review covers recent advances in the field of liquid biomarkers and computed tomographic imaging features, with special attention to new methods for combination of biomarkers as well as the use of artificial intelligence for the discrimination of benign from malignant nodules.