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This Podcast features an interview Arthur Weiss and Jayajit Das, senior authors of a Research Article that appears in this issue of Science Signaling. Signaling through the B cell receptor (BCR) may be induced by monomeric or multimeric ligands and requires kinases of both the Src and Syk family. A group led by Weiss and Das used mathematical modeling to address the roles of these two kinases in B cell receptor signaling. Their findings, which were experimentally validated in cells, indicated that Syk was sufficient to mediate signaling initiated by multimeric ligands, which induce BCR clustering. However, both kinases were required to mediate signaling initiated by monomeric ligands, which do not induce BCR clustering.