Waddington's original description of canalization refers to the ability of an organism to maintain phenotypic fidelity in the face of environmental and/or genetic perturbation. Development of the human brain requires exposure to a ‘wild-type’ environment—one that supports the optimal set of instructions for development. Recently derived brain structures in our species, such as the expanded neocortex, may be more vulnerable to decanalization because there has been insufficient time to evolve buffering capacity. On the basis of modern notions of decanalization, we provide perspectives on selected environmental and genetic risk factors for schizophrenia, and we discuss strengths and weaknesses of this conceptual framework. We argue that if we are to build a solid foundation for translational psychiatry, we must explore models that attempt to capture the complexity of the interaction between genetic and non-genetic risk factors in mediating and modulating brain development.