Cell chemotaxis requires the acquisition and maintenance of both spatial and functional asymmetry between initially equivalent cell parts. In leukocytes one becomes the leading edge and the other, the rear edge or uropod. The acquisition of this cell polarity is controlled by an array of chemoattractants, including those of the chemokine family. We propose that chemokine receptor activation in highly organized lipid raft domains is a major determinant for the correct localization of the signaling pathways leading to the cell asymmetries required for migration. The lateral organization imposed by membrane raft microdomains is discussed in the context of other chemokine receptor activities, such as its role as a human immunodeficiency virus (HIV) coreceptor.