The AP-2α transcription factor is required for multiple aspects of vertebrate development and mice lacking the AP-2α gene (tcfap2a) die at birth from severe defects affecting the head and trunk. Several of the defects associated with the tcfap2a-null mutation affect neural crest cell (NCC) derivatives including the craniofacial skeleton, cranial ganglia, and heart outflow tract. Consequently, there is considerable interest in the role of AP-2α in neural crest cell function in development and evolution. In addition, the expression of the AP-2α gene is utilized as a marker for premigratory and migratory neural crest cells in many vertebrate species. Here, we have specifically addressed how the presence of AP-2α in neural crest cells affects development by creating a conditional (floxed) version of tcfap2a which has subsequently been intercrossed with mice expressing Cre recombinase under the control of Wnt1 cis-regulatory sequences. Neural crest-specific disruption of tcfap2a results in frequent perinatal lethality associated with neural tube closure defects and cleft secondary palate. A small but significant fraction of mutant mice can survive into adulthood, but have retarded craniofacial growth, abnormal middle ear development, and defects in pigmentation. The phenotypes obtained confirm that AP-2α directs important aspects of neural crest cell function. At the same time, we did not observe several neurocristopathies affecting the head and heart that might be expected based on the phenotype of the AP-2α-null mouse. These results have important implications for the evolution and function of the AP-2 gene family in both the neural crest and the vertebrate embryo.