This lecture presents circulating tumor DNA (ctDNA) as a quantitatively scarce subset of cell free DNA and contrasts tumor informed with tumor naïve assay approaches before applying these frameworks to NSCLC. It integrates emerging evidence that early on treatment ctDNA dynamics—whether decline, clearance, or persistence—during chemo immunotherapy or immunotherapy alone can stratify risk in metastatic disease and may eventually guide maintenance or adaptive treatment decisions, while underscoring that phase III level validation for routine use is still lacking. The discussion then shifts to MRD detection in resectable NSCLC, emphasizing real world sensitivity limitations and advocating for longitudinal, multi timepoint sampling and prospective escalation/de escalation trials as prerequisites for widespread clinical adoption.