ALK-rearranged lung cancer defines a distinctive molecular cohort of patients whose outcomes are significantly improved by the availability of ALK inhibitors. Thus, it is imperative for clinicians to screen appropriate patients for this driver mutation with a molecular testing platform capable of capturing all ALK fusions. Here, we report a novel VKORC1L1-ALK fusion and an ALK T1151K resistance mutation detected in a lung cancer patient who had been on crizotinib for over 8 years. Alectinib induced a dramatic response in this patient demonstrating its clinical activity against T1151K. This case illustrates the importance of performing repeat biopsy to explore mechanism(s) of resistance when patients experience disease progression on an ALK inhibitor. The approach has a direct therapeutic impact particularly when an ALK resistance mutation is identified.