Molecular profiling of tumors from patients plays a crucial role in precision oncology. While tumor tissue-based genomic testing remains the gold standard in clinical management of patients with non-small cell lung cancer, advances in genomic technologies, the analysis of various bodily fluids, mainly blood but also saliva, pleural/pericardial effusions, urine, and cerebrospinal fluid is now feasible and readily available. In this review, we will focus on the clinical application of circulating tumor DNA (ctDNA) in patients with non-small cell lung cancer in the setting of early-stage disease, locally advanced disease with attention to the potential of ctDNA in prognostication, risk stratification, minimal residual disease, and in advanced disease, its role in the detection of genomic markers and mechanisms of acquired resistance. The role of ctDNA and liquid biopsies in lung cancer screening will also be discussed.