Detergent-resistant membrane domains (DRMs) can be isolated from a variety of eukaryotic cells. DRMs are of interest because of their potential importance in processes such as intracellular membrane sorting, and signal transduction at the cell surface. One type of DRM is also present in caveolae, non clathrin-coated plasma membrane pits with proposed roles in endocytosis, lipid transport, and signal transduction. Here we review recent advances in understanding the structure of these domains, and explore the possibility that DRMs are present in a phase separate from the surrounding bilayer. DRMs are rich in sphingolipids and cholesterol. The long saturated acyl chains and high acyl chain melting temperature of sphingolipids mediate their association in detergent resistant domains. These sphingolipid and cholesterol-rich domains have the properties of the liquid-ordered phase previously described in model membranes. Several lines of investigation support the idea that DRMs are not detergent-induced artifacts, but exist as domains in cell membranes. A striking feature of the proteins in DRMs is that many of them are linked to lipids. These include both GPI anchored proteins, and acylated proteins such as Src-family kinases. The linkage of these proteins to saturated acyl chains may help in targeting them to ordered membrane domains. Caveolin, the major structural protein of caveolae, is multiply palmitoylated. The presence of a high concentration of palmitate chains in DRMs in caveolae may help stabilize ordered domains.