Receptor-activity modifying proteins (RAMPs) belong to a single family of transmembrane proteins. RAMPs determine ligand specificity of G-protein coupled receptors; calcitonin receptor and the calcitonin-receptor like receptor (CLR). To date, three members of RAMP family (RAMP-1, -2, -3) have been identified. The co-expression of RAMP-1 with CLR constitutes the calcitonin gene related peptide receptor whereas the association of the RAMP-2 or RAMP-3 with CLR forms the adrenomedullin (AM) receptor. Alterations in signaling and subcellular distribution of G-protein coupled receptors can be responsible for the regulation of many disease conditions. These changes may be mediated by the different isoforms of RAMPs associated with such receptors. In this chapter, we describe the differential responses associated with upregulation of RAMPs in disease conditions. For instance, the upregulation of all three RAMP isoforms contributes to the cardioprotective effects of the CLR/RAMP ligands. On the other hand, strong evidence exists for the involvement of AM in various cancers and that its action is mediated by the upregulation of RAMP isoforms, RAMP-2 and -3. Though limited, a few studies have been reported on the differential response associated with the upregulation of RAMP in other disease conditions such as sepsis, liver cirrhosis, glomerulonephritis, Type 1 diabetes and Parkinson's disease. Thus, the regulation of RAMP expression is involved in the pathophysiology associated with various diseases.