Background: The role of olfactory marker protein (OMP), a hallmark of mature olfactory sensory neurons (OSNs), has been poorly understood since its discovery. The electrophysiological and behavioral phenotypes of OMP knockout mice indicated that OMP influences olfactory signal transduction. However, the mechanism by which this occurs remained unknown. Principal Findings: We used intact olfactory epithelium obtained from WT and OMP-/- mice to monitor the Ca2+ dynamics induced by the activation of cyclic nucleotide-gated channels, voltage-operated Ca2+ channels, or Ca2+ stores in single dendritic knobs of OSNs. Our data suggested that OMP could act to modulate the Ca2+-homeostasis in these neurons by influencing the activity of the plasma membrane Na+/ Ca2+-exchanger (NCX). Immunohistochemistry verifies colocalization of NCX1 and OMP in the cilia and knobs of OSNs. To test the role of NCX activity, we compared the kinetics of Ca2+ elevation by stimulating the reverse mode of NCX in both WT and OMP2/2 mice. The resulting Ca2+ responses indicate that OMP facilitates NCX activity and allows rapid Ca2+ extrusion from OSN knobs. To address the mechanism by which OMP influences NCX activity in OSNs we studied protein-peptide interactions in real-time using surface plasmon resonance technology. We demonstrate the direct interaction of the XIP regulatory-peptide of NCX with calmodulin (CaM). Conclusions: Since CaM also binds to the Bex protein, an interacting protein partner of OMP, these observations strongly suggest that OMP can influence CaM efficacy and thus alters NCX activity by a series of protein-protein interactions. © 2009 Kwon et al.