Although the major biochemical events triggered by ligation of the B-cell receptor (BCR) have been well defined [1,2], little is known about the spatio-temporal organization of BCR signaling components within the cell membrane and the mechanisms by which signaling specificity is achieved. Partitioning of signaling complexes into specialized domains in the plasma membrane may provide a mechanism for channeling specific stimuli into distinct signaling pathways. Here, we report that multiple tyrosine-phosphorylated proteins accumulate transiently upon BCR activation in detergent-insoluble membrane microdomains known as lipid rafts. We found an activation-dependent translocation to the rafts of the BCR itself, as well as phospholipase Cγ2 (PLCγ2), an enzyme critical for BCR-induced Ca2+ flux in B cells. An intact raft structure was required for BCR-induced tyrosine phosphorylation of PLCγ2 and the induction of Ca2+ flux. Taken together, these data provide a functional role for lipid rafts in BCR signaling.