Recently, we have shown that small cell lung cancer (SCLC) is dependent on activation of Hedgehog signaling, an embryonic pathway implicated in development, morphogenesis and the regulation of stem cell fates. These findings form the framework for an emerging view of cancer as a process of aberrant organogenesis in which progenitor/ stem cells escape dependence on niche signaling through mutation in genes such as Ptch, or through persistent activation of progenitor cell pathways. Interestingly, the normally quiescent airway epithelial compartment uses the Hh pathway to repopulate itself when challenged by injury. How Hh signaling works to promote the malignant phenotype promises to be as important biologically as the promise of Hh pathway inhibitors are clinically.