Disruption of putative enhancers downstream of the human short stature homeobox (SHOX) gene is thought to cause the limb defects characteristic of Léri–Weill dyschondrosteosis. Since the closely related mouse Shox2 gene has a similar function in limbs, we used a comparative approach to search for enhancer sequences responsible for driving limb expression of the Shox genes in mice and humans. Unexpectedly, transgenic analysis demonstrated that the most conserved enhancer sequences near the Shox genes were active in the central nervous system (CNS), suggesting an ancient function for these genes in this tissue. Given the results of the transgenic screens, and since Shox2 was shown to be expressed in the CNS, the major goal of this thesis became to explore the functional role of Shox2 in brain development and test the developmental and behavioural consequences of loss- and gain-of-function of Shox2 in mouse models. Using a conditional knockout strategy, we demonstrated that elimination of Shox2 in the brain results in developmental defects in the inferior colliculus and cerebellum. Specifically, loss of Shox2 in the cerebellum results in precocious differentiation and migration of granule cell precursors (GCPs). We showed that Shox2 is required for normal sonic hedgehog (Shh) expression in dorsal-residing Purkinje cells. In addition, the bone morphogenetic protein 4 (Bmp4) expression domain was expanded in Shox2-deficient animals, suggesting that Shox2 plays a key role in the proper interplay between cross-repressive SHH and BMP signalling. Moreover, loss of Shox2 causes behavioural abnormalities, including reduced exploratory activity, altered gait and impaired motor coordination. Furthermore, we demonstrated that elimination of Shox2 in the brain results in the loss of medially located visceral motor neurons (vMNs) in the facial motor nucleus. This correlates with impaired axonal projection properties of vMNs, which appears as improper branching and peripheral target acquisition of the facial (VII) nerves. Shox2-mutant neonates also displayed impaired feeding behaviour, likely due to improper development of the facial (VII) nerves. Together, these works have uncovered a novel function for Shox2 during hindbrain development. The Shox2-mutant model can now be exploited to further our understanding of neurogenesis, specification and circuit formation in the hindbrain.