The Hedgehog (Hh) signaling pathway is critical for embryonic development. In 
adult tissues, Hh signaling is relatively quiescent with the exception of roles 
in tissue maintenance and repair. Aberrant activation of Hh signaling is 
implicated in multiple aspects of transformation, including the maintenance of 
the cancer stem cell (CSC) phenotype. Preclinical studies indicate that CSCs 
from many tumor types are sensitive to Hh pathway inhibition and that 
Hh-targeted therapeutics block many aspects of transformation attributed to 
CSCs, including drug resistance, relapse, and metastasis. However, to date, Hh 
inhibitors, specifically those targeting Smoothened [such as vismodegib, 
BMS-833923, saridegib (IPI-926), sonidegib/erismodegib (LDE225), PF-04449913, 
LY2940680, LEQ 506, and TAK-441], have demonstrated good efficacy as monotherapy 
in patients with basal cell carcinoma and medulloblastoma, but have shown 
limited activity in other tumor types. This lack of success is likely due to 
many factors, including a lack of patient stratification in early trials, 
cross-talk between Hh and other oncogenic signaling pathways that can modulate 
therapeutic response, and a limited knowledge of Hh pathway activation 
mechanisms in CSCs from most tumor types. Here, we discuss Hh signaling 
mechanisms in the context of human cancer, particularly in the maintenance of 
the CSC phenotype, and consider new therapeutic strategies that hold the 
potential to expand considerably the scope and therapeutic efficacy of 
Hh-directed anticancer therapy.