Multiple myeloma (MM) is a deadly plasma cell cancer that resides in the bone marrow (BM). Numerous studies have demonstrated the involvement of the BM microenvironment supporting tumor growth, angiogenesis, bone disease and drug resistance. Reciprocal interactions between the different components of the BM microenvironment and the MM cells are necessary to regulate migration, differentiation, proliferation and survival of the malignant plasma cells. In this review we focus on the interactions and molecular mechanisms by which the BM microenvironment exert these effects. Better understanding of these interactions and the study of the epigenetic changes that tumor cells undergo are necessary in order to improve current treatments and for the discovery of new therapies that may eventually lead to a potential cure.