Recent work has given rise to a fundamentally new way of thinking about biological membranes. Contrary to earlier views, we now know that lipids do not always mix homogeneously in membranes, but can be organized into domains in the bilayer. The best-characterized membrane domains, called rafts, are rich in cholesterol and sphingolipids. The ability of certain proteins to associate with these domains has profound effects on their function. This new realization has implications in fields as diverse as signal transduction, protein and lipid sorting, and cell adhesion and motility. For instance, following antigen stimulation of T lymphocytes, the T cell receptor and its signaling partners must cluster together in rafts to initiate the signal transduction cascade. Our lab has developed a model for raft structure, and for how proteins and lipids associate with rafts, that is now generally accepted in the field. This model provides a conceptual foundation for further exploration of raft structure and function. We use a combination of cell biological, biochemical, and biophysical methods to study rafts in cells and model membranes.