Initially, it was thought that there was no intracellular signaling mediated by NRP‐1 alone in response to its ligands. However, the emerging data from our group as well as others suggest that the signaling through NRP‐1 actually promotes angiogenesis and is mediated through its C‐terminal domain and downstream molecules such as phosphoinositide 3‐kinase. Hence, understanding the signal transduction pathways mediated by NRP‐1 and identification of its downstream molecules are of importance. By using both in vivo zebrafish model and in vitro tissue culture system, we have shown that the C‐terminal three amino acids of NRP‐1 (SEA‐COOH) are required for NRP‐1‐mediated angiogenesis. Furthermore, knocking down of RGS‐GAIP‐interacting protein C terminus (GIPC) in zebrafish, which is associated with C‐terminal domain of NRP‐1, exhibits similar vasculature phenotypes to those from NRP‐1 null. Specific and effective silencing of GIPC in vascular endothelium results in inhibition of NRP‐1‐mediated migration. In both cases as described, PDZ domain of GIPC is responsible for its function. Taken together, our data suggest a novel role of GIPC in angiogenesis and vessel formation and also support our hypothesis that NRP‐1 can facilitate downstream signaling to promote angiogenesis through GIPC.—Wang, L., Mukhopadhyay, D., Xu, X. C terminus of RGS‐GAIP‐interacting protein conveys neuropilin‐1‐mediated signaling during angiogenesis. FASEB J. 20, E732–E741 (2006)