In B cells, antigen drives the formation of B-cell receptor (BCR) clusters that initiate the formation of signaling complexes associated with the cytoplasmic domains of the BCRs. These signaling active complexes contain a number of protein and lipid kinases and phosphatases and adapter and scaffolding proteins that together function to trigger downstream signaling cascades leading to the activation of a variety of genes associated with B-cell activation. Although we are learning a considerable amount about the molecular details of the assembly of immune receptor signaling complexes, as reviewed in this volume, a fundamental question remains, namely how does antigen binding outside the cell initiate the assembly of signaling complexes inside the cell. For B cells, we do not yet understand how the information that the ectodomain of the BCR has bound to an antigen is translated across the membrane to induce changes in the cytoplasmic domains that trigger the assembly of signaling complexes. Here we describe what is known about the initiation of the antigen-driven BCR signal transduction in the newly emerging context of B-cell recognition of antigens presented by antigen-presenting cells in lymphoid tissues. We also discuss a recently proposed model for the initiation of BCR signaling termed the 'conformation-induced oligomerization model' and address the implications of this model for the mechanisms by which BCR signaling may be modulated by adapters and coreceptors.