The microenvironment in which a tumor initiates, plays a critical role in tumor progression. Stroma consists of extracellular matrix and cells. Among the identified cells, are endothelial cells (EC). The dialogue of EC with tumor cells (TC) is played at multiple levels and in a highly specialized way. On the one hand, the endothelial lining provides a “go/no-go” signal to TC, closely controlling their metastatic potential; on the other hand, microenvironment may switch toward an angiogenic profile. In solid tumours, hypoxia is the major trigger of angiogenesis; as a result, vessels are immature and leaky. The mechanisms leading to BM angiogenesis in hematological malignancies, including Multiple Myeloma (MM), are presently unknown; a key element is that ??MMBM is hypoxic by nature.