Neuronal and retinal tissues are high in phospholipids containing one or two long chain polyunsaturated acyl chains. These studies are directed towards determining a molecular basis for the modulation of G protein-coupled receptor signaling by phospholipids containing polyunsaturated acyl chains, in particular 22:6n-3. Studies are also focused on the response of these phospholipids to the acute exposure to ethanol. Fluorescence Energy Transfer (FRET) studies have demonstrated lateral domain formation in bilayers containing di16:0 and di22:6 PCs plus cholesterol, which was dependent on the presence of both cholesterol and rhodopsin. The role of lateral domain formation in bilayers of 22:6n-3 containing lipids is being further investigated. Both acyl chain free volume and curvature stress have been invoked as bilayer properties, which modulate membrane protein function. Experiments indicate an inverse relationship between these two properties, suggesting that they may have opposite effects with respect to modulating protein function. Recent studies have implicated lateral heterogeneity in cholesterol distribution as a driving force for domain formation in biological membranes. In order to determine the role of phospholipid composition in the formation of these domains, the partitioning of cholesterol into bilayers of defined lipid composition was studied. A novel method of measuring cholesterol partitioning into lipid bilayers was developed. These studies indicate that cholesterol partitioning is determined by both phospholipid head group and acyl chain composition. Polyunsaturated acyl chains are among the most effective in reducing the level of cholesterol in lipid membranes, while trans fatty acids increase membrane cholesterol content. These studies are important in developing and understanding the role of 22:6n-3 acyl chains in domain formation, the modulation of membrane protein function, and the health benefits and deficits associated with polyunsaturated fatty acids and trans fatty acids, respectively.