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These downloadable slides examine the evolving management of ROS1-rearranged non-small cell lung cancer (NSCLC) after progression on initial ROS1-targeted therapy, with a focus on mechanisms of resistance, central nervous system disease, and selection of subsequent treatment. The content covers guideline-based approaches to limited versus systemic progression and summarizes efficacy and safety data for later-line ROS1 inhibitors, including lorlatinib and repotrectinib, with attention to intracranial activity and outcomes in patients with prior TKI exposure. The activity also explores on-target and off-target resistance mechanisms, including the clinically important ROS1 G2032R solvent-front mutation, bypass signaling pathways, and histologic transformation, and considers how these findings may inform treatment selection at progression. Finally, emerging ROS1-directed strategies and combination approaches are discussed to help learners interpret developing evidence and individualize therapy for patients with treatment-resistant ROS1-positive NSCLC.