Crystal structures are available for ligand-free and small molecule antagonist-bound CLR:RAMP1 and ligand-free CLR:RAMP2 ECD complexes, but these provide little insight into how peptides bind or how RAMPs determine selectivity (Kusano et al., 2012; ter Haar et al., 2010). Extensive mutagenesis on the RAMPs (Qi and Hay, 2010) only provided clear evidence for the involvement of one RAMP residue (RAMP1 W84) in the binding of CGRP and two residues (RAMP2 F111 and E101) for AM binding (Moore et al., 2010; Watkins et al., 2014). It has not been possible to interpret these data mechanistically. A further complication is that it appears unlikely that CGRP and AM bind as extended helices as seen with other class B peptide ligands; there is evidence that only a small portion of these peptides form α helices and that at their C termini, there are one or more turn structures (Breeze et al., 1991; Carpenter et al., 2001; Pérez-Castells et al., 2012; Watkins et al., 2013b). Consequently, the mechanism of RAMP action and the mode of binding of CT family peptides remain unknown. Here, we describe high-resolution crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 ECD heterodimers that reveal bound peptide conformations starkly different from other class B GPCR peptide ligands, explain how RAMPs determine peptide selectivity, and provide molecular templates to guide drug development targeting CLR:RAMP complexes.