Zoledronic acid and pamidronate are two potent anticatabolic nitrogen-containing bisphosphonates (BPs) used extensively in diseases with high bone turnover such as multiple myeloma (MM). In this review we focus on their biology and their current and future use in MM, and highlight some of the most common and emerging side effects. Although the primary target cells for BPs are osteoclasts, new insights suggest other cell types of the bone microenvironment as possible targets, including osteoblasts, endothelial cells, immune cells, and cancer cells. Here, we focus on the current guidelines for the use of BPs in MM and address side effects such as renal toxicity, osteonecrosis of the jaw, and low-energy fractures. Finally, we approach the future of BP use in MM in the context of other bone-targeted agents, evaluating ongoing clinical trials addressing alternate dosing and schedules of BP administration in MM patients.