Targeted therapy has become a valuable approach in adenocarcinoma of the lung. The number of actionable mutations has been continuously increasing with significant acceleration from discovery to clinical application. Herein, we present a case of innovative treatment using targeted therapy of a 75-year-old female with two primary adenocarcinomas of the lung. The first tumor was found to carry an activating mutation in the exon 19 of the epidermal growth factor receptor and responded favorably to treatment with erlotinib. The second primary tumor was found to carry an isolated amplification of the c-met gene but no epidermal growth factor receptor mutation. Off-label use of crizotinib, a potent inhibitor of c-met, was prescribed. Within 4 weeks of treatment initiation, the tumor and the dependent lymphadenopathy responded with rapid shrinkage. This observation stresses the need for rebiopsy of tumors upon progression or change of biological behavior for selection of appropriate targeted therapy.