Background: Cancer treatment has witnessed a paradigm shift due to identification of driver mutations at the genetic level with cognate targeted therapies to negate the same. Development of acquired resistance is however, inevitable. Case Report: We present the case of a non-small cell lung (NSCLC) cancer patient with ROS1 gene rearrangement who developed acquired resistance to crizotinib. Conclusion: This case brings into light the rare NSCLC patient with ROS1 gene rearrangement in Indian population.