Multiple myeloma is a hematological malignancy inwhich clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic le-sions due to increased osteoclast(OC) activity and sup-pressed osteoblast(OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells(MSCs) play a critical role in multiple myeloma patho-physiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of my-eloma bone disease(MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients(pMSCs) and their healthy counterparts(dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibi-tory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and ac-tivity at various levels(i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncou-pling ephrinB2-EphB4 signaling, and through augment-ed production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents(at preclinical or clinical stage) targeting those signaling pathways is commented. Multiple myeloma is a hematological malignancy inwhich clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic le-sions due to increased osteoclast (OC) activity and sup-pressed osteoblast (OB) function is characteristic of the disease. The bone marrow, mesenchymal stromal cells (MSCs) play a critical role in multiple myeloma patho-physiology, strongly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of my-eloma bone disease (MBD), together with the reported genomic, functional and gene expression differences differences between MSCs derived from myeloma patients (pMSCs) and their healthy counterparts (dMSCs). progenitors of OBs, pMSCs to contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequences of multiple OB inhibi -tory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs, include, contribute to MBD by promoting OC formation and ac-tivity at various levels (ie, increasing RANKL to OPG expression, augmenting secretion of activin A, uncou- pling ephrinB2-EphB4 signaling, and through augment-ed production of Wnt5a), which further contribute to OB / OC uncoupling in osteolytic lesions. In this review, we also look past the main signaling pathways involved in the osteogenic differentiation of MSCs and / or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents (at preclinical or clinical stage) targe those signaling pathways is commented.