A simplified overview of B cell development. Differentiation is initiated in the bone marrow in an antigen-independent manner and is completed in the periphery in response to antigenic challenge. Rearrangement of the Ig heavy chain is initiated in pro–B cells and involves sequential D_H to J_H and V_H to DJ_H rearrangements. Once light chain rearrangement is completed, B cells emigrate to the periphery and give rise to multiple peripheral lineages (not shown). Peripheral B cells activated by either T cell–dependent or T cell–independent antigens differentiate into plasma cells. In this issue, Zhang et al. (15) demonstrate that IRE1 is required for V(D)J recombination early in B cell development, but in a kinase- and endoribonuclease-independent fashion. IRE1 kinase and endoribonuclease activities are required for the splicing of XBP1 and plasma cell development. Pre-BCR, pre–B cell receptor.