Natural antibodies are spontaneously arising polyreactive Ig, usually IgM, that are encoded by V genes in germline configuration and are produced by B-1 cells. Because of their ability to promiscuously bind to a variety of antigens, especially those on bacteria and viruses, natural antibodies act as a primary line of defense against infection. A key shortfall in our understanding of these key effector molecules centers on the molecular mechanisms regulating natural antibody secretion by B-1 cells. Recent advances in our understanding of plasmacytic differentiation now provide us with a conceptual framework by which we can begin to explore this issue. In the studies described herein, we demonstrate that secreting B-1 cells utilize some aspects of the plasmacytic differentiation program and deviate away from it in others. Specifically, we show that key repressors of the plasmacytic program, BCL-6 and PAX-5a, are indeed reduced in secreting B-1 B cells. Surprisingly, we found that key promoters of the plasmacytic program, BLIMP-1 and XBP-1, are not upregulated in secreting B-1 B cells. These data demonstrate that B-1 B cells operate under a differentiation program unique from prototypic secreting B-2 cells and cast BCL-6 and PAX-5a but not BLIMP-1 and XBP-1 as central regulators of natural immunoglobulin secretion.