To evaluate potential new therapies and targets for treating multiple myeloma (MM), reproducible, biologically relevant in vivo models are required. Preclinical in vivo models of human MM allow investigators to evaluate novel therapies alone and in combination and quickly translate these results to the clinic where patients directly benefit, whether in the form of a new clinical trial, new doses and schedules, or new drug combinations. Presented in this unit are protocols for generating and maintaining a human extramedullary MM tumor in mice. Additionally, the extramedullary tumor can be excised and digested into a single-cell suspension and the human MM cells injected into mice subcutaneously, intravenously, or intratibially. Once these tumors are generated, they can be used to evaluate novel anti-MM agents and other therapies.