Despite advances in therapeutic approaches, lung cancer remains the leading cause of cancer-related deaths. To understand the molecular programs underlying lung cancer initiation and maintenance, we focused on stem cell programs that are normally extinguished with differentiation but can be reactivated during oncogenesis. Here we have used extensive genetic modeling and patient-derived xenografts to identify a dual role for Msi2: as a signal that acts initially to sensitize cells to transformation, and subsequently to drive tumor propagation. Using Msi reporter mice, we found that Msi2-expressing cells were marked by a pro-oncogenic landscape and a preferential ability to respond to Ras and p53 mutations. Consistent with this, genetic deletion of Msi2 in an autochthonous Ras/p53-driven lung cancer model resulted in a marked reduction of tumor burden, delayed progression, and a doubling of median survival. Additionally, this dependency was conserved in human disease as inhibition of Msi2 impaired tumor growth in patient-derived xenografts. Mechanistically, Msi2 triggered a broad range of pathways critical for tumor growth, including several novel effectors of lung adenocarcinoma. Collectively, these findings reveal a critical role for Msi2 in aggressive lung adenocarcinoma, lend new insight into the biology of this disease, and identify potential new therapeutic targets.