The three tandem-arrayed protocadherin (Pcdh) gene clusters, namely Pcdh-a, Pcdh-ß and Pcdh-, play important roles in the development of the vertebrate central nervous system. To gain insight into the molecular action of Pcdhs, we performed a systematic proteomic analysis of Pcdh--associated protein complexes. We identified a list of 154 non-redundant proteins in the Pcdh- complexes. This list includes nearly 30 members of clustered Pcdh -a, -ß and - families as core components of the complexes and additional over 120 putative Pcdh associated proteins. We validated a selected subset of Pcdh--associated proteins using specific antibodies. Analysis of the identities of Pcdh associated proteins show that the majority of them overlap with the proteomic profile of postsynaptic density preparations. Further analysis of membrane protein complexes reveals several validated Pcdh--associated proteins exhibit reduced levels in Pcdh- deficient brain tissues. Therefore, Pcdh-s are required for the integrity of the complexes. However, the size of the overall complexes and the abundance of many other proteins remain unchanged, raising a possibility that Pcdh-as and Pcdh-ßs might compensate for Pcdh- function in complex formation. As a test of this idea, RNAi knock-down of both Pcdh-as and Pcdh-s show that Pcdhs have redundant functions in regulating neuronal survival in the chicken spinal cord. Taken together, our data provide evidence that clustered Pcdhs coexist in large protein complexes and have overlapping functions during vertebrate neural development.