Myeloma cells typically reside in the bone marrow. Their presence induces two types of manifestations, both resulting from myeloma plasma cells interactions with cells in their immediate microenvironment: local manifestations such as lytic bone disease, and systemic manifestations such as suppression of the immune system and anemia. Recently, it has been demonstrated that in addition to producing morbid manifestations, these interactions with the bone marrow microenvironment are essential for the survival and growth of the myeloma plasma cells, highlighting a reciprocal relationship that sustains the disease process and promotes progression. The discussion that follows will concentrate on myeloma-induced changes in the bone marrow microenvironment that are important for disease subsistence and progression, with emphasis on data obtained from in vivo and ex vivo studies with primary myeloma cells.