The past 9 years have seen a remarkable shift in the diagnostic and therapeutic approach to lung carcinomas, beginning with the discovery of EGFR mutations and their role in directing management with targeted tyrosine kinase inhibitors. This special review recounts the experiences at one molecular diagnostic testing center, the Brigham and Women's Hospital/Dana-Farber Cancer Institute, from the initial research observations in 2003 to the development of multigene next-generation sequencing in 2012. Throughout this time, the activities in the molecular diagnostics laboratory have been in a state of rapid flux, responding to changes in clinical needs and scientific discoveries.