It is now two decades since Rituximab was first used in the treatment of patients with systemic lupus erythematosus. There have been many challenges but in spite of failing to meet its primary endpoints in two clinical trials it is widely used for many aspects of lupus, its side-effects and the possibility that combining it with Benlysta may be of value. We also consider the proposal that it may provide a useful initial therapy. In this review, we consider the place of Rituximab in the treatment of lupus and anticipate how developments in fully-humanized anti-CD20 monoclonals may well extend the "therapeutic life" of B-cell depletion as a viable treatment option.