A large number of genes have been isolated in the last few years that seem to be involved in the processes of induction, specification and regionalization of the brain. The generation of mouse mutant models for such genes has provided a powerful tool of analysis into their in-vivo properties. Among these genes, Otx1 and Otx2 play a crucial role in several processes of brain morphogenesis. Otx2 is required in the early specification of the neuroectoderm destined to become the fore-midbrain, Otx1 is required mainly for correct corticogenesis, and both genes co-operate in patterning the developing brain through a gene-dosage dependent mechanism. Furthermore, an extensive functional equivalence occurs between the mammalian Otx genes and their Drosophila homolog, orthodenticle. This appears particularly fascinating when considering the huge differences between the brains of mice and flies. This review deals with the major aspects related to the involvement of Otx1 and Otx2 in the development of the mammalian brain and, in particular, of the cerebral cortex.