The pcdhalpha/CNR gene comprises a diverse array of neuronal cell-surface proteins of the cadherin superfamily, although very little is known about their role in neural development. Here we provide the first in-depth characterization of pcdh1alpha in zebrafish. Whole-mount immunocytochemistry demonstrates that a large proportion of endogenous cytoplasmic domain immunoreactivity is present in the nucleus, suggesting that endoproteolytic cleavage and nuclear translocation of the intracellular domain are important aspects of pcdh1alpha activity in vivo. Using whole-mount immunocytochemistry and BAC-based expression of Pcdh1alpha-GFP fusion proteins, we find that Pcdh1alpha does not appear to form stable, synaptic puncta at early stages of synaptogenesis. We also demonstrate that the presence of the Pcdh1alpha cytoplasmic domain is essential for normal function. Truncation of Pcdh1alpha proteins, using splice-blocking antisense morpholinos to prevent the addition of the common intracellular domain to the entire pcdh1alpha cluster, results in neuronal apoptosis throughout the developing brain and spinal cord, demonstrating an essential role for pcdh1alpha in early neural development. This cell death phenotype can be attenuated by the expression of a soluble Pcdh1alpha cytoplasmic domain.