Zinc deficiency has been associated with neural tube defects, both through epidemiological studies in human populations and experimental analysis in mouse. This relationship, however, is poorly understood, particularly in terms of the mechanistic link between a lack of zinc and failure of neural tube closure. Lee Niswander and colleagues now address this link by investigating the consequences of acute zinc depletion in mouse embryos cultured ex vivo and in cultured neuroepithelial cells. Upon treatment of embryos with a zinc chelator, neural tube closure fails, and massive apoptosis can be observed in the neuroepithelium. The authors hypothesise that this may be due, at least partly, to dysregulation of p53, and indeed find that p53 levels are rapidly increased upon zinc depletion. Mechanistically, this can be attributed to impaired Mdm2-mediated ubiquitylation of p53, consistent with the fact that zinc binding in the C terminus of Mdm2 is important for its enzymatic activity. The authors further show that it is ectopic transcriptional activity of p53, rather than its binding to anti-apoptotic proteins, that is primarily responsible for the observed apoptosis. Although other mechanisms may contribute to the defects that are observed upon zinc depletion, these data uncover an important pathway by which zinc levels regulate neural tube closure in the developing embryo.