The severe combined immune deficient human (SCID-hu) myeloma model is the only available model in which primary myeloma cells grow in vivo in a human bone marrow microenvironment. A SCID mouse receives an implanted human fetal bone into which myeloma cells are directly injected. Through interaction with the human bone marrow microenvironment, the myeloma cells induce typical myeloma manifestations in the SCID host, such as the appearance of M protein in the serum, and changes in the implanted human bone, which often result in osteolysis of the human bone. The model provides the only platform for in vivo investigation of the biology and therapy of primary human myeloma in a human microenvironment. This chapter describes in detail all the steps necessary to establish this model and evaluate its success.