Cancers that metastasize or grow in the bone marrow are typically considered incurable and cause extensive damage to the bone and bone marrow. The bone is a complex, dynamic, three-dimensional (3D) environment composed of a plethora of cells that may contribute to, or constrain, the growth of tumor cells and development of bone disease. The development of safe and effective drugs is currently hampered by pre-clinical two-dimensional (2D) models whose poor predictive power does not accurately predict the success or failure of therapeutics. These inadequate models often result in drugs proceeding through extensive pre-clinical studies only to fail clinically. Consistently, 3D co-culture systems prove superior to 2D mono-cultures in modeling in vivo cell phenotypes, disease progression and response to therapeutics. As a complex, multicellular, multidimensional bone microenvironment, 3D models allow for more accurate predictions of tumor growth, cell-cell and cell-matrix interactions, and resulting therapeutic responses. In this review we will discuss various 3D models available and describe step-by-step protocols for two of the most well-established 3D culture models for studying tumor-induced bone disease.