Multiple myeloma (MM) is a B-cell malignancy characterized by an excess of monotypic plasma cells which localize almost exclusively in the bone marrow provoking bone destruction via the activation of the osteoclasts. The bone marrow microenvironment, mainly through stromal cells, is strictly involved in the evolution of the disease supporting MM cell growth and survival [1]. MM plasma cells reside in the bone marrow by binding to adhesion molecule of extracellular matrix (ECM) and stromal cells. The activation of some signaling pathways within the stromal cells increases the production of several cytokines which in turn favors the myeloma cell proliferation and survival [2-6], and enhance the drug resistance by anti-apoptotic mechanisms [1,7-9]. Novel therapeutic agents target not only the myeloma cells but also the interaction between MM cells and the bone marrow microenvironment [8]. Bisphosphonates (Bps) interfere as well with bone microenvironment inhibiting the survival of stromal cells and hampering the contact between plasma and stromal cells. In this review we will revise preclinical evidences, and the potential mechanisms of the antitumor activity of zoledronic acid.