Bisphosphonates are clinically used inhibitors of bone resorption. Previous studies have noted an increase in humoral immune responses in bisphosphonate-treated mice. Investigating this phenomenon in vesicular stomatitis virus-infected mice, the authors found that bisphosphonates increased neutralizing antibody levels (both IgM and IgG) by 100-fold compared with controls. Similarly, bisphosphonates increased antibody responses to proteins, haptens and existing commercial vaccine formulations. Bisphosphonates were shown to directly target B cells, and although the mechanism of this adjuvanticity remains to be determined it was independent of the Toll-like receptor and inflammasome pathways. Of note, patients with skeletal disease had a transient but significant increase in total IgG levels following a single intravenous infusion of bisphosphonates. Thus, bisphosphonates are B cell-targeting adjuvants that could be readily combined with vaccines, given that bisphosphonates are already widely used in the clinic.