Adrenomedullin (AM) is a recently discovered, potent vasodilatory peptide with activities including maintenance of cardiovascular and renal homeostasis. Studies have indicated that AM is important in initiating the hyperdynamic response during the early stage of sepsis, and reduction of the vascular effects of AM marks the transition from the initial hyperdynamic phase to the late hypodynamic phase in experimental sepsis. The decreased AM responsiveness in late sepsis may be related to alterations in the AM receptor binding characteristics and/or signaling pathways. Genetic experiments have provided useful information by enhancing AM gene expression. Moreover, a plasma protein which binds AM, adrenomedullin binding protein-1 (AMBP-1), was reported very recently and is just beginning to be investigated as an important modulator in the biphasic septic response. In this regard, our recent results have demonstrated that AMBP-1 synergistically enhanced AM-induced vascular relaxation in both sham and septic animals. It appears that decreased levels of AMBP-1 play a critical role in producing vascular AM hyporesponsiveness during the late stage of sepsis. Furthermore, administration of AM and AMBP-1 in combination prevented the transition from the hyperdynamic to hypodynamic response during the progression of polymicrobial sepsis. Thus, modulation of vascular responsiveness to AM by AMBP-1 may provide a novel approach for the management of sepsis.