Developmental disorders are the number one cause of infant mortality in the US and Europe and the impact on child health is lifelong. Each birth defect is rare but collectively structural birth defects are highly common. Recent advances in genetic sequencing have greatly improved our chances of linking gene variants to birth defects. However, assigning disease causality remains difficult, which is further complicated by a lack of understanding of how gene variants lead to disease mechanism. To address this challenge, gene discovery must be coupled with mechanism discovery. Birth defects research requires a collaborative understanding of patient phenotype, genetic variation and biological mechanisms. In order to fully utilize the genetic information, we need to understand the relevance of any genetic variant to the disease phenotype. This requires communication between clinicians (such as clinical geneticists, dysmorphologists, pediatricians) and research biologists (such as genomicists, epidemiologists, developmental, cellular and molecular biologists). We need animal models to study structural birth defect candidate genes, and given the large number of candidate genes identified, non-mammalian animal models as well as cell/iPSC modeling for rapid screening. The ultimate goal is to better understand the molecular and cellular pathogenesis in order to improve diagnosis and treatment for patients and to identify preventative strategies.