Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide. While target therapies have changed the outcomes of patients harboring actionable mutations, resistance inevitably emerges. Circulating tumor DNA (ctDNA) offers a minimally invasive tool for capturing tumor evolution in real time. This approach enables the rapid detection of resistance mechanisms, complements or substitutes for tissue re-biopsy, and reduces the burden of invasive procedures for patients. In this review, we summarize the current evidence on the use of liquid biopsy to uncover resistance mechanisms in patients progressing on targeted therapies, with a focus on its role in dynamic tumor profiling and longitudinal disease monitoring.