There is great interest in developing plasma based tests which could either define patients who are at risk for the development of lung cancer, or could diagnose the undefined nodule on an imaging examination with high sensitivity and specificity. In the United States, the Early Detection Research Network (EDRN) of the National Cancer Institute represents a group of individuals funded by the government to specifically perform these investigations. This requires very well annotated registries, the ability to accumulation patient’s blood, tumor and normal matching tissue, peripheral blood lymphocytes, as well as proper control specimens from patients at high risk for lung cancer that are followed in screening programs, or from patients who have had a resection for a presumed lung cancer which proves not be malignant. This lecture will discuss the organization in the United States of the lung group of the EDRN, and highlight some of the protocols used for the discovery of these biomarkers. We will specifically cover the most promising results using microRNA, various proteomic platforms, as well as the investigation of novel components of the circulation including microvescicles and exosomes. Although many of these biomarker profiles are studied in university medical centers, some have been discovered in collaboration with diagnostic industrial partners. We will discuss the use of biomarkers in the blood not only for the diagnosis of lung cancer and mesothelioma, but also for their prognosis, and which of these biomarkers are undergoing validation prospectively in the clinic.