The relaxin-like peptides produce their effects by acting at four G-protein-coupled receptors (GPCRs) RXFP1 to 4. RXFP1 and 2 are characterized by large extracellular domains containing leucine-rich repeats, whereas RXFP3 and 4 closely resemble small-peptide-liganded GPCRs. Studies with mutant RXFP1 receptors established that the final 10 amino acids of the C-terminus and Arg(752) in particular are obligatory for the second phase of cAMP signaling. Examination of the importance of cell type revealed different patterns of cAMP signaling related to the types of G-proteins expressed in these cells. Studies of RXFP3 signaling using reporter genes revealed that both relaxin and relaxin-3 activated the receptor but displayed different patterns of signaling. The studies suggest that the functional domains of the receptor, the cell type in which it is expressed, and the ligand used to activate the receptor all have important roles in determining the functional response observed.