Stem cell function is central for the maintenance of normal tissue homeostasis. Here we show that deletion of p38α mitogen-activated protein (MAP) kinase in adult mice results in increased proliferation and defective differentiation of lung stem and progenitor cells both in vivo and in vitro. We found that p38α positively regulates factors such as CCAAT/enhancer-binding protein that are required for lung cell differentiation. In addition, p38α controls self-renewal of the lung stem and progenitor cell population by inhibiting proliferation-inducing signals, most notably epidermal growth factor receptor. As a consequence, the inactivation of p38α leads to an immature and hyperproliferative lung epithelium that is highly sensitized to K-Ras^G12V-induced tumorigenesis. Our results indicate that by coordinating proliferation and differentiation signals in lung stem and progenitor cells, p38α has a key role in the regulation of lung cell renewal and tumorigenesis.