An overview of clinically unmet needs that exist following the National Lung Screening Trial. While there is a reduction in both lung cancer mortality and all-cause mortality when using low-dose CT, there are still two major unmet needs highlighted by the trial. The first is the need to limit the number of people who are screened with low-dose CT to those with the highest risks. Genetic, transcriptomic and epigenetic screening biomarkers could meet this need by identifying smokers with the highest likelihood of developing lung cancer. The second unmet need comes from the high number of nodules identified by CT, which are false positives for lung cancer. Early diagnostic biomarkers could play a key role in identifying which nodules are likely to be cancerous before sending patients into surgery.