What distinguishes polyunsaturated fatty acids (PUFAs) from less unsaturated fatty acids is the presence of a repeating =CH-CH(2)-CH= unit that produces an extremely flexible structure rapidly isomerizing through conformational states. Docosahexaenoic acid (DHA) with 6 double bonds is the most extreme example. The focus of this review is the profound impact that the high disorder of DHA has on its interaction with cholesterol when the PUFA is incorporated into membrane phospholipids. Results from a battery of biophysical techniques are described. They demonstrate an aversion of DHA for the sterol that drives the lateral segregation of DHA-containing phospholipids into liquid disordered (l(d)) domains that are depleted in cholesterol. These domains are compositionally and organizationally the antithesis of lipid rafts, the much-studied liquid ordered (l(o)) domain that is enriched in predominantly saturated sphingolipids and cholesterol. We hypothesize that the introduction of DHA-rich domains into the plasma membrane where they coexist with lipid rafts is the origin, in part, of the astonishing diversity of health benefits that accrue from dietary consumption of DHA. According to our model, changes in the conformation of signaling proteins when they move between these disparate domains have the potential to modulate cell function.