Lung cancer is the leading cause of cancer-related death for both men and women in the U.S. As for many other cancer types, lung cancer is not a single disease, but rather a variety of diseases that present different histopathological, molecular and clinical characteristics. Improved diagnostic and therapeutic tools are needed to manage and treat lung cancer patients. microRNAs are a recently discovered class of short, noncoding RNAs that constitute a novel and functionally important layer of gene regulation. Using new mouse transgenic models for lung cancer, Liu and colleagues reported a genome-wide microRNA expression analysis and identified a signature of down-regulated microRNAs in lung cancer tissues relative to adjacent normal lung. This signature was validated in clinical specimens from lung cancer patients, underscoring the relevance of this profile to human lung cancer. In vitro experiments demonstrated that restoring miR-34c, miR-145, or miR-142-5p expression markedly diminished proliferation of lung cancer cell lines. Here, we discuss the clinical implications of these findings for lung cancer biology, therapy, and prevention.