Membrane-cytoskeleton coupling is known to play major roles in a plethora of cellular responses, such as cell growth, differentiation, polarization, motility, and others. In this review, the authors discuss the growing amount of evidence indicating that membrane-cytoskeleton interactions are regulated by the lipid composition of the plasma membrane, suggesting that cholesterol-rich membrane domains (lipid rafts), including caveolae, are essential for membrane-cytoskeleton coupling. Several models for raft-cytoskeleton interactions are discussed. Also described is the evidence suggesting that raft-cytoskeleton interactions play key roles in several cytoskeleton-dependent processes, particularly in the regulation of cellular biomechanical properties. To address further the physiological significance of raft-cytoskeleton coupling, the authors focus on the impact of oxidized low density lipoproteins, one of the major cholesterol carriers and proatherogenic factors, on the integrity of lipid rafts/caveolae, and on the organization of the cytoskeleton. Finally, the authors review the recent studies showing that oxLDL and cholesterol depletion have similar impacts on the biomechanical properties of vascular endothelial cells, which in turn affect endothelial angiogenic potential.