Hedgehog (HH), Notch, and Wnt signaling are key stem cell self-renewal pathways that are deregulated in lung cancer and thus represent potential therapeutic targets (i). Agents inhibiting the hedgehog pathway include monoclonal antibodies against HH ligand and cyclopamine, which is a small molecule inhibitor of smoothened (SMO). Monoclonal antibodies against Wnt ligand and frizzled (FZD) receptor and inhibitors of protein complexes mediating Wnt signaling, such as Wnt-FZD or β-catenin–transcription factor (β-Cat-TCF), are examples of ways of targeting the Wnt pathway. Strategies of blocking or silencing Notch signaling can be either selective, such as the targeting of individual Notch receptors with antisense or monoclonal antibodies, or nonselective, such as the use of soluble receptor decoys that sequester Notch ligands or γ-secretase inhibitors. Solid and dashed arrows represent multiple components of these pathways that, for simplicity, are not detailed here. These components also represent potential therapeutic targets. Other methods of targeting cancer stem cells include immunotherapy-based approaches against antigens present on cancer stem cells (ii); targeting cancer stem cell mechanisms of resistance to cytotoxic therapy by inhibiting DNA repair enzymes such as the checkpoint kinases (Chk1, Chk2) (iii); targeting stem cell–specific survival mechanisms with telomerase inhibitors (GRN163L) (iv); and inducing stem cell differentiation with soluble factors such as bone morphogenetic proteins (BMPs) (v). GLI, glioma-associated oncogene; GLI^ACT, active form of GLI; GLI^REP, repressor form of GLI; NICD, Notch intracellular domain; CSL, CBF1, suppressor of hairless, Lag-1; TACE, TNF-α–converting enzyme; ADAM10, a disintegrin and metalloprotease domain 10; PTCH, patched homolog; GSK3β, glycogen synthase kinase 3β; CSK1α, cyclin-suppressing kinase 1; DSH, dishevelled.