Multiple myeloma (MM) is a poorly understood and uniformly fatal malignancy of antibody-secreting plasma cells (PC). Although several key molecular events in disease initiation or progression have been confirmed (such as 14q32 translocations) or implicated (chromosome 13 deletion), a unifying mechanism of myelomagenesis has proved elusive. Furthermore, while MM is generally indistinguishable morphologically, the disease exhibits tremendous variability in its clinical course, with some patients surviving only months and others many years, suggesting that MM is composed of distinct clinical entities. As abnormal gene expression is central to most, if not all cancers, high-throughput global gene expression profiling has become a powerful tool to investigate the molecular biology and clinical behavior of malignancy. Here we discuss recent progress made in the development of molecular-based diagnostics and prognostics for MM through the dissection of the transcriptome of PCs from healthy individuals and patients with MM and other PC dyscrasias.