One characteristic of Down syndrome and the Ts65Dn mouse is a smaller and hypocellular cerebellum. The canonical Sonic Hedgehog (Shh) pathway is important for cerebellar development, and, now, Roger Reeves and colleagues show that a single treatment of Tn65Dn mice with a Hedgehog agonist leads to normal cerebellum in adults (Sci. Transl. Med. 5, 201ra120, 2013). SAG 1.1 (SAG), a known Shh pathway agonist, binds and activates Smoothened, thereby activating the canonical Shh pathway. This molecule crosses the blood-brain barrier and can activate the proliferation of granule cell precursors in newborn mice. The authors administered SAG to newborn Ts65Dn mice and found that, at 15 weeks of age, SAG-injected mice had the same density of granule cells as control mice. Interestingly, despite the obvious morphological normalization of SAG-injected Ts65Dn mice, long-term depression originating in cerebellar Purkinje cells was not normalized. Nevertheless, behavioral tests showed that SAG-injected Ts65Dn mice had significant improvements in hippocampal tasks involving learning and memory but not in prefrontal tasks. Although the results suggest that SAG may have a therapeutic role in Down syndrome, further work needs to proceed with caution, as activating the Shh pathway in newborns may have deleterious effects, given the known role of Shh stimulation in medulloblastoma.