Gene expression profiling is a powerful tool through which the biology of multiple myeloma can be dissected. We will describe in this chapter how early studies using this technology have provided meaningful insights into myeloma biology, have led to the identification of new therapeutic targets, and have identified powerful prognostic and pharmacogenomic markers. Specifically, we will demonstrate that gene expression profiling can be used to segregate myeloma patients into prognostic categories within which known IgH translocation signatures can be readily defined. We also show that expression signatures can identify patients with chromosome 13 deletion. Finally, we demonstrate that global gene expression signatures can be distilled to short lists of three genes or more which together impart clinical outcome information, which is significantly more powerful than any previously defined prognostic tool. Expression profiling has also led to the identification of a number of new therapeutic targets not only in myeloma cell survival but also in the pathogenesis of the osteolysis which is a hallmark of this disease.