The development of the plasma cell tumor (PCT) model was the first widely accepted in vivo model of multiple myeloma (MM). Potter and colleagues used this chemically induced PCT model to study the pathophysiology of malignant plasma cells and also used it to screen anti-MM agents. Two decades later the C57BL/KaLwRij mouse strain was found to spontaneously develop MM. Testing of pamidronate using this endogenously arising MM model revealed significant reductions in MM-associated bone disease, which was subsequently confirmed in human trials in MM patients. Transgenic models have also been developed in which the MM is localized in the bone marrow causing lytic bone lesions. Experiments in a transgenic model showed that a new oral proteasome inhibitor was effective at reducing MM burden. A clinical trial later confirmed this observation and validated the model. The xenograft model has been used to grow human MM in immunocompromised mice. The xenograft models of MM have been very useful in optimizing drug schedules and doses, which have helped in the treatments given to MM patients. However, in vivo models have been criticized for having a low clinical predictive power of new chemical entities (NCEs). Despite this, the knowledge gained from in vivo models of MM has without a doubt benefited MM patients.