Bisphosphonates inhibit osteoclast-mediated bone resorption and have been used extensively to prevent skeletal-related events in patients with bone lesions from multiple myeloma (MM). In addition, in vitro and in vivo preclinical data suggest that bisphosphonates also have antimyeloma properties that may induce myeloma cell apoptosis, activate an anticancer immune response, inhibit angiogenesis, and reduce tumor burden, supporting an expanded role for bisphosphonates. Signals for improved survival in the clinic first emerged in retrospective analyses of MM patient subgroups in larger clinical trials. Recently, improved progression-free survival and overall survival with bisphosphonates have been reported in the overall populations of large-scale randomized clinical trials. Several ongoing clinical trials will help further define the role of bisphosphonates during antimyeloma therapy. Overall, bisphosphonates appear to be well tolerated in patients with MM; the most common adverse events are mild and can be easily managed. However, emphasis on renal monitoring and preventive dentistry are necessary to reduce the risk of potential adverse events, and have become the standard of care for patients with MM.