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The plasma membrane of a mammalian cell is an asymmetric bilayer of phospholipids and cholesterol. The cells invest considerable amount of energy to conserve this feature as the asymmetry is important for cellular functions. The membrane hosts a variety of proteins and regulates the transport in and out of the cell. In this work, we used cyclodextrins to facilitate phospholipid exchange with the bilayer membrane of red blood cells to investigate and alter the cell-cell and cell-particle interactions. Cyclodextrins are cyclic molecules with a hydrophilic external structure and a hydrophobic internal cavity. Due to their chemical structure, cyclodextrins can form complexes with hydrophobic or amphiphilic molecules, including lipids. This property has resulted in the widespread use of cyclodextrins for characterization and manipulation of lipids in biological membranes. In the chapter one, we discuss the use of cyclodextrins for characterization of lipids in the cell plasma membrane. First, the chemical structure of different cyclodextrins is explained. Then, the current knowledge on the mechanisms of cyclodextrin-lipid interaction and the role of cyclodextrin and lipid chemical structure in the outcome of such interactions is summarized. The use of cyclodextrins for manipulation of plasma membrane lipids and its application to study membrane lipid rafts is also reviewed. Analysis of the lipid composition of the outer leaflet is important for understanding cell membrane biology in health and disease. In the second chapter, a method based on cyclodextrin-mediated lipid exchange to characterize the phospholipids in the outer leaflet of red blood cells (RBCs) is reported. Methyl-α-cyclodextrin, loaded with exogenous lipids, was used to extract phospholipids from the membrane outer leaflet, while delivering lipids to the cell to maintain cell membrane integrity. Thin layer chromatography and lipidomics demonstrated that the extracted lipids were from the membrane outer leaflet. Phosphatidylcholines (PC) and sphingomyelins (SM) were the most abundant phospholipids in the RBCs outer leaflet with PC 34:1 and SM 34:1 being the most abundant species. Fluorescence quenching confirmed the delivery of exogenous lipids to the cell outer leaflet. As use of new nanoparticles in our everyday life is increasing, the need to understand the effects of these particles on different cells increases. In the third chapter, we proposed use of cyclodextrin-mediated phospholipid exchange to develop a comprehensive model for studying cell-particle interactions. We exchanged the outer leaflet membrane of RBCs with six different phospholipids to investigate the effects of phospholipid saturation and headgroup on the interaction of RBCs with nanoparticles. Thin layer chromatography was used to confirm the exchange and fluorescent anisotropy, flow cytometry, and fluorescent microscopy was performed to determine the mechanism of interactions. Our results indicated that use of exchanged RBCs can resolve issues associated with conventional model membranes such as overrepresenting the cell curvature or underrepresenting membrane proteins and cellular cytoskeleton.We also investigated using phospholipid exchange for extending the shelf life of RBCs. When RBCs are stored for long periods of time (senescent RBCs), phosphatidylserine (PS), a phagocyte recognition marker, translocates from the inner leaflet of the membrane to the outer leaflet. This prohibits transfusion of such RBCs. The developed phospholipid exchange method was utilized to remove PS and reconstitute the outer leaflet with SM and PC. Removal of PS was confirmed using flow cytometry of stained RBCs with a fluorescent PS marker. Macrophages derived from THP-1 cells and peripheral blood mononuclear cells, phagocytosed senescent RBCs with reconstituted membranes in significantly lower amounts compared to control cells. This demonstrates the efficiency of the phospholipid exchange process and its application in modifying cell-cell interactions. We also investigated oxygen affinity and fluorescent anisotropy of the membrane of RBCs before and after exchange and reported that the phospholipid exchange does not alter the functionality of the RBCs.