Circulating tumor DNA (ctDNA) consists of short, double-stranded DNA fragments that are released into the circulation by tumor cells. With the advent of newer molecular platforms, ctDNA can be detected with high sensitivity and specificity in plasma. The assay’s noninvasive nature, ability to reflect intratumoral heterogeneity, short turnaround time, and ability to obtain serial samples make it an attractive option compared with traditional tissue biopsy tumor sequencing. Currently, this technology is mostly being used for the detection of EGFR mutations in patients with advanced non–small-cell lung cancer where tissue is inadequate to detect EGFR mutations that drive acquired resistance, most notably EGFR T790M. Emerging uses include the incorporation of ctDNA testing into primary diagnosis, treatment monitoring, detection of minimal residual disease, and detection of early-stage disease in screening populations. This review summarizes both validated and evolving uses of ctDNA testing in non–small-cell lung cancer in the context of oncologists’ daily practice and some of its potential challenges in the era of targeted therapy and immunotherapy.