Our understanding of the multiple physiological and pathological functions of B-cells continues to expand at a fascinating rate. A critical part of this expanding knowledge is the realization that B-cells can be responsible, at least in part, for diseases in which they had not been previously suspected and that their pathogenic influence can be mediated by multiple mechanisms. In turn, the availability of effective agents capable of inducing profound and long-lasting B-cell depletion and the safety and efficacy of Rituximab in non-Hodgkin lymphoma has prompted investigators to use this therapeutic approach in a large number of autoimmune diseases. Thus far, the results have been very promising, and in some cases nothing short of spectacular. In this review, we shall discuss the roles of B-cells in health and disease and the available evidence regarding the efficacy of B-cell depletion in human autoimmunity. Finally, we will discuss some of the many challenges and opportunities that the medical and scientific community should address in the foreseeable future.