Significance Familial dysautonomia (FD) is a devastating developmental peripheral autonomic and sensory neuropathy caused by a mutation in the gene inhibitor of kappa B kinase complex-associated protein ( IKBKAP ). It is marked by tachycardia, blood pressure lability, autonomic vomiting “crises,” and decreased pain and temperature sensation. FD is progressive, and affected individuals commonly die during early adulthood. To identify the cellular and molecular mechanisms that cause FD, we generated a mouse model for the disease in which Ikbkap expression is ablated in the neural crest lineage. This study is a mechanistic analysis of the cellular events that go awry in the developing peripheral nervous system in FD and identifies essential functions of IKAP protein in the peripheral nervous system.