Anti-double-stranded DNA (dsDNA) B cells persist even in non-autoimmune-prone animals. In this review, we summarize data regarding the activation potential of these cells. Provision of cognate CD4 T cell help to anti-dsDNA B cells in nonautoimmune mice not only drives their maturation and entry into the B cell follicle, but also leads to secretion of anti-dsDNA autoantibodies. Intriguingly, if T regulatory cells are provided along with T helper cells, the antibody response of anti-dsDNA B cells is diminished. We have also found that T-independent stimulation with CpG oligodeoxy-nucleotides leads to the proliferation and enhanced recovery of anti-dsDNA B cells in vitro. These data suggest that control of anti-dsDNA antibody production may rely on elements from both the innate and adaptive arms of the immune system.