The hedgehog (HH) family of growth factors is involved in many aspects of growth and development, from the establishment of left–right axes at gastrulation to the patterning and formation of multiple structures in essentially every tissue, to the maintenance and regulation of stem cell populations in adults. Sonic hedgehog (Shh) in particular acts as a mitogen, regulating proliferation of target cells, a growth factor that triggers differentiation in target populations, and a morphogen causing cells to respond differently based on their positions along a spatial and temporal concentration gradient. Given its very broad range of effects in development, it is not surprising that many of the structures affected by a disruption in Shh signaling are also affected in Down syndrome (DS). However, recent studies have shown that trisomic cerebellar granule cell precursors have a deficit, compared to their euploid counterparts, in their response to the mitogenic effects of Shh. This deficit substantially contributes to the hypocellular cerebellum in mouse models that parallels the human DS phenotype and can be corrected in early development by a single exposure to a small-molecule agonist of the Shh pathway.Here, we consider how an attenuated Shh response might affect several aspects of development to produce multiple phenotypic outcomes observed in DS.