Adrenomedullin (AM) is a multifunctional peptide with a range of cardiovascular functions including direct effects on cardiomyocytes. Despite the demonstration of high numbers of AM binding sites in rat heart, the receptor responsible for cardiac AM action has not been characterized. We show here that the hearts of adult and neonatal rats, and neonatal cardiomyocyte cultures coexpress mRNA transcripts for the calcitonin receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMPs). RAMP2 mRNA predominated over RAMP1 in adult (20:1 ratio) and neonatal heart (10:1 ratio), and in cardiomyocyte cultures (1.7:1 ratio), though the relative abundance of these transcripts appears to be developmentally regulated. Transient transfection of cardiomyocytes using a cAMP-responsive element (CRE)-luciferase reporter gene as an indirect measure of cAMP activation, demonstrated that overexpression of either CRLR or RAMP2 potentiated the AM signalling response. Overexpression of CRLR and RAMP2 together led to an additive effect on AM signalling that was approximately 4-fold greater than control cardiomyocytes stimulated with AM. Furthermore, the AM-mediated induction of CRE-luciferase activity was abolished by coincubation with the receptor antagonist CGRP(8-37) or by overexpression of a CRLR antisense construct. These data demonstrate that AM action in the rat cardiomyocyte requires CRLR and RAMP2 to constitute functional AM receptors.