We have used human embryonic stem cells as models for pediatric diseases. We have identified enzymes that modify key cellular regulators with a small protein ubiquitin and that are essential for differentiation of hESCs into particular cell types. In our most exciting avenue of work, we have identified a novel developmental switch that is required for the generation of neural crest cells, a transient and migratory cell population that is essential for craniofacial development. This developmental switch is controlled by ubiquitylation, i.e. modification of cellular proteins with ubiquitin, and the essential targets are mutated in a developmental disease of abnormal craniofacial development that is observed 1 in every 50,000 births. We have investigated the molecular mechanism underlying the role of ubiquitylation in neural crest cell formation, and found results that could point towards a novel therapeutic strategy against a catastrophic pediatric disease.