Patched (Ptc) is a 12-cross membrane protein that binds the secreted Hedgehog protein. Its regulation of the Hedgehog signaling pathway is critical to normal development and to a number of human diseases. This report analyzes features of sequence similarity and divergence in the Ptc protein family and identifies two subtypes distinguished by novel conserved domains. We used these results to propose a rational basis for classification. We show that one of the conserved sequence regions in the C-terminal domain of Ptch1 is responsible, at least in part, for rapid turnover. This sequence is absent in the stable Ptch2 protein.