Lung squamous cell carcinoma (LSCC) represents 30% of all lung cancers but has few effective treatments available. Now, Alan Fields and colleagues identify a novel signaling axis specific to LSCC that has implications for the development of new treatment options (Cancer Cell 25, 139–151, 2014). The authors previously identified PRKCI as an oncogene overexpressed in lung cancers with an amplification of chromosome 3q26. In this study, the authors establish that PRKCI is overexpressed, and its product, protein kinase Cι (PKCι), was activated in five cell cultures of isolated stem-like cells from lung cancer cell lines. They further showed that PKCι regulates the Hedgehog pathway in these cultures to stimulate proliferation and to maintain a stem-like phenotype in vitro and drive tumor formation in vivo. Further, they found that the LSCC oncogene SOX2, a known master regulator of stem cell maintenance, was frequently coamplified with PRKCI in human cancers. Through a series of meticulous experiments, they showed that PKCι phosphorylates a novel site in SOX2 (Thr118), leading to SOX2 occupancy of the HHAT promoter and thereby activating Hedgehog signaling. Disruption of the Thr118 phosphorylation site abolished PKCι-dependent Hedgehog signaling and diminished tumor cell proliferation in vitro. These results implicate PKCι and HHAT inhibitors as strong candidates for the treatment of LSCC.