Dandy-Walker Malformation (DWM) is a common malformation of the cerebellum in humans. While it can be diagnosed by prenatal magnetic resonance imaging (MRI) using radiological criteria, almost nothing is known about the developmental mechanisms which elicit Dandy-Walker Malformation. Therefore, we sought to use a wide spectrum of techniques to understand the underlying cause of this malformation. We obtained 27 cases diagnosed as either DWM or Cerebellar Vermis Hypoplasia (CVH), another common cerebellar malformation. Using a combination of radiological, histopathological, and transcriptomic analyses we were able to determine the developmental pathogenesis of DWM. Our analysis included atypical measurements of different aspects of the cerebellar development, including growth and foliation of the cerebellar midline called vermis, proliferation in various germinal zones, and morphobiometric changes. Furthermore, we found that an important stem cell zone called the rhombic lip, which produces nearly 80% all neurons of the adult human brain, is specifically disrupted in DWM. Finally, transcriptomic analysis revealed specific genes related to normal growth and cell division were downregulated in the DWM cerebellum. Using this information, we propose a model for how DWM arises during development, and hypothesize that a disruption to the germinal rhombic lip by vascular insults causes a reduction in cell proliferation, resulting in the characteristic presentation of DWM that can be seen on MRI. We acknowledge that although mouse models have provided us many clues on how the cerebellum develops, they have many limitations since they lack critical germinal zones present during human development. Our study underlines the urgency for further human-based analysis of brain birth defects.