Introduction The calcitonin family peptides probably act through G-protein coupled membrane receptors. The gene for calcitonin receptors has been cloned. It is homologous to GPCRs in family "B" which typically recognizes regulatory peptides (secretin, glucagons, VIP). Recently, a homolog of calcitonin receptor, CRLR (calcitonin-receptor-like receptor human 461 aa; rat/mouse 463 aa) was identified. CRLR has 55% homology with calcitonin receptor. It is now shown that CRLR can function as either a CGRP receptor or an ADM receptor, depending upon which members of a new family of proteins called receptor activity modifying proteins (RAMP1-3) are expressed. RAMPs1-3 contains an N-terminal signal peptide, an extracellular N-terminus, a single transmembrane domain near the C-terminus, and cytoplasmic C-terminus. RAMP1-3 displays 31% identity. RAMPS may be involved in the transport of CRLR to the plasma membrane. RAMP1 (human, mouse, rat 148 aa) presents the CRLR receptor as a glycoprotein that function as CGRP receptor. RAMP1 is expressed in many tissues, including the uterus, bladder, brain, pancreas, and GI tract. CRLR and RAMP1 are not co-expressed in all tissues suggesting that their co-expression may define which cells express functional CGRP receptors. RAMP2 (human 175 aa; rat 182 aa, and mouse 189 aa)-transported receptors are core-glycosylated and function as ADM receptor. It is expressed in the lung, breast, immune system and fetal tissues. RAMP3 is most abundant in the kidney and lung.