Lung cancer is the leading cause of cancer deaths worldwide, with smoking as the main risk factor. The use of low-dose computed tomography (LDCT) as a screening method has shown a 20% lung cancer specific mortality benefit; however, widespread implementation is estimated to add $1.3–$2.0 billion in annual national health care expenditures. Blood-based microRNAs (miRNAs) have been investigated in detail and found to be potentially useful biomarkers indicating the presence of lung cancer, especially when used as a companion test to LDCT. Testing for miRNAs and circulating tumor DNA (ct-DNA) in the blood are anticipated to become more affordable in the near future, and therefore these potentially sensitive methods could serve as first-line screening modalities prior to obtaining LDCT and definitive diagnostic tests for lung cancer. Furthermore, miRNAs may shed light not only on the tumor burden, but also perhaps on tumor aggressiveness, histology, treatment response and the patient's overall survival. In the near future, analysis of ct-DNA may reveal somatic mutations beyond EGFR, tumor burden and the presence of occult progression of disease. In theory, these biomarkers may also help oncologists to elucidate the tumor response to radiotherapy, and in the future, may assist the radiation oncologist in making data-driven treatment decisions and providing patients with quantitative information regarding their treatment response.