Lymphoid cell differentiation relies on precisely orchestrated gene activation and repression events. Gene targeting studies have demonstrated crucial roles for the transcription factors Ikaros and Aiolos in regulating multiple stages of B and T cell development. Recent experiments suggest that Ikaros and Aiolos set B cell antigen-receptor (BCR)- and TCR-mediated signaling thresholds and that the molecules exist within T cells in nuclear complexes that contain nucleosome remodeling and histone deacetylase activities.