Aberrant activation of Hedgehog (Hh) signaling causes about 25% of medulloblastomas (MB), the most common solid malignancy of childhood. Expression analyses of Hh MB cohorts (n=85) revealed overexpression of ILK) in 12% of cases. SmoM2 is an activated mutant of the Hh effector, Smoothened (Smo), originally identified in human Hh-initiated cancers. Math1 is selectively expressed in cerebellar granule cell precursors, MB cells of origin. We crossed Math1-Cre mice with mice carrying a floxed, SmoM2[fl/fl] allele, a well-characterized model of Hh-initiated MB. These mice developed MB with 100% penetrance and mean survival of 42 days after birth (8% surviving at d42, n=12). Targeted ablation of ilk[fl/fl] in Math1-Cre;SmoM2 cerebellae increased the survival time of tumour-bearing mice to 47 days after birth (70% surviving at d42, n=10, P=0.013). Math1-Cre-mediated ILK knockout phenocopied Smo knockout in the embryonic cerebellum (E18.5), and both these knockouts inhibited activation of Hh signalling in GCPs. The primary cilium is a cellular signalling organelle required for normal Hh signalling and for growth of Smo-driven MB. ILK has been identified as a ciliary protein, and we confirmed localization of endogenous ILK in primary cilia by immunocytochemistry. In ciliated cell models siRNA-mediated silencing, or a selective small molecule ILK inhibitor, blocked Hh-stimulated transport of Smo into primary cilia, required for signalling. Bimolecular fluorescence complementation demonstrated close specific (< 30nm) association of ILK and Smo in the primary cilium, suggesting that ILK mediates signalling via direct interaction with Smo. We are currently evaluating the effect of ILK knockout in a second model of MB caused by activation of normal Smo signalling. Our data identify ILK as a mediator of developmental Hh signalling, contributing to MB pathogenesis and representing a novel therapeutic target in Hh cancers.