Recent gene expression profiling using high throughput sequencing and microarray analysis of multiple myeloma has shed new light on this morphologically homogeneous yet clinically heterogeneous disease. The biology of the disease has been interrogated in studies, which reveal that patients have unique gene expression clusters that correlate with disease severity. These studies have also revealed that some myeloma cells have gene expression characteristics that resemble the molecular profile of late-stage B cells. Expression profiling can identify hallmark immunoglobulin translocations and other common structural genetic changes that impart prognostic significance. Molecular profiling has been demonstrated to be of value in pharmacogenomic studies predicting response to therapy and revealing novel therapeutic targets. These studies are providing insight into many previously unexplained features of this difficult disease.