Molecular profiling holds great promise for improving our ability to diagnose, prognosticate, and select individualized treatments for lung cancer patients. However, using multidimensional data and novel technologies to derive these profiles is limited by our ability to employ the assay in a clinical scenario where it can impact the course of disease. Although many molecular signatures have been reported in lung cancer, as of yet, few have been sufficiently validated for widespread clinical use. Recently, several novel signatures have been reported, which address critical aspects of patient care and/or demonstrate improved efforts for appropriate clinical validation. Here, we present our opinion on the current state of the field of molecular signatures in lung cancer.