Multiple myeloma (MM) is the second most common hematological malignancy and is characterized by the clonal expansion of plasma cells in the bone marrow. Recently, hypoxia has received increased interest in the context of MM, in both basic and translational research. In this review, we describe the discovery of the hypoxic niche in MM and how it can be targeted therapeutically. We also discuss mouse models that closely mimic human MM, highlighting those that allow preclinical research into new therapies that exploit the hypoxic niche in MM.