Recent advances in our understanding of B-cell dysregulation and its important link to autoimmunity have brought about a radical change in the management of autoimmune diseases. Over the past few years, encouraging data from several clinical trials of rituximab, a chimeric anti-CD20 antibody, have led to its approval for use in rheumatoid arthritis (RA). These data, regarding clinical efficacy, safety, improved patient-reported outcomes and cost-effectiveness with the use of rituximab in patients with RA, have led to the exploration of other agents targeting B-cell functions. Ocrelizumab, a novel humanized anti-CD20 antibody, has shown clinical efficacy and safety in a recently reported trial in patients with RA. Future clinical trials will help evaluate further the role of ocrelizumab in RA and its potential use in other autoimmune diseases. This review describes current understanding of B-cell therapy, the role of rituximab in the treatment of RA and the evolving role of ocrelizumab as a B-cell-targeted therapy.