Organotypic brain tissue slice cultures are a powerful tool in which to perform perturbation experiments of ASD-relevant genes and assess phenotype in a highly relevant context. The developing mammalian brain is a tremendously complex organ in which disruptions of genes can result in context- and time-dependent effects that manifest at multiple levels, many of which are difficult to model using other approaches. Understanding the roles that specific genes play in this complex and inaccessible physiological context has been a significant challenge historically. Ex vivo organotypic brain tissue slice cultures offer the opportunity to translate high-confidence candidates from molecular and network studies to a tissue model that preserves in vivo-like context as well as a relevant organism level context for assessing the impacts of genetic and chemical perturbations. This allows us to take the next step in translating basic science to potential therapeutic leads.