Analogous to the successful introduction of biologic agents to treat rheumatoid arthritis, it was widely envisaged that similar successful studies would follow in systemic lupus erythematosus (SLE), as much was known about the etiopathogenesis of the disease and appropriate agents to block the key cells and molecules were available. The reality, however, has been different. The failure of rituximab, a monoclonal antibody that induces B-cell depletion, to meet its primary and secondary end points in trials of nonrenal SLE (EXPLORER) and renal (LUNAR) lupus nephritis has been disappointing given the success reported in many open-label studies. Concluding that B-cell-depletion therapy is not effective in SLE seems rather extreme. Further analysis of the as-yet unpublished results and their comparison with data from published studies might provide insight into whether B-cell depletion will eventually be accepted as a useful approach for the treatment of SLE.