Although not exclusive, mounting evidence supports the fact that DNA methylation at CpG dinucleotides controls B-cell development and the progressive eliminati or inactivation of autoreactive B cell. Indeed, the expression of different B ce specific factors, including Pax5, rearrangement of the B-cell receptor (BCR) and cytokine production are tightly controlled by DNA methylation. Among normal B cells, the autoreactive CD5+ B cell sub-population presents a reduced capacity to methylate its DNA that leads to the expression of normally repressed genes, such as the human endogenous retrovirus (HERV). In systemic lupus erythematosus (SLE) patients, the archetype ofautoimmune disease, autoreactive B cells are characterized by their inability to induce DNA methylation that prolongs their survival. Finally, treating B cells with demethylating drugs increased their autoreactivity. Altogether this suggests that a deeper comprehension ofDNA methylation in B cells may offer opportunities to develop new therapeutics to control autoreactive B cells.