<p>Antibody–drug conjugates (ADCs) are complex molecules composed of a monoclonal antibody, a linker and a cytotoxic payload. Their design enables the selective delivery of cytotoxic agents to tumoral cells through antibody binding to a tumor-expressed antigen, followed by internalization, intracellular degradation and payload release, ultimately enabling the cytotoxic drug to exert its antitumor activity. ADCs have been evaluated in phase II and III trials in previously treated advanced non-small cell lung cancer (NSCLC), both in oncogene-addicted and in non-oncogene-addicted tumors, addressing resistance to standard therapies. Ongoing clinical trials are now expanding their use both in the first-line setting for advanced disease and in earlier disease stages. This narrative review summarizes the currently available data for ADC treatment in NSCLC, highlighting the need for improved patient selection to maximize benefit while limiting toxicity, incorporating clinical characteristics, pharmacogenomics and optimal treatment sequencing in the equation. Moreover, the understanding of resistance mechanisms and the development and validation of predictive biomarkers will be of utmost relevance to inform clinical practice.</p>