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Summary:  Multiple myeloma (MM) is a rare but uniformly fatal malignancy of antibody-secreting plasma cells (PCs). Although several key molecular events in disease initiation or progression have been confirmed (e.g. FGFR3/MMSET activation) or implicated (e.g. chromosome 13 deletion), the mechanisms of MM development remain enigmatic. Importantly, although generally being indistinguishable morphologically, MM exhibits a tremendous degree of variability in clinical course, with some patients surviving only months and others many years. However, current laboratory parameters can account for no more than 20% of this outcome variability. Furthermore, the means by which current drugs impart their anti-MM effect are also mostly unknown. In addition, the mechanisms by which MM cells contribute to serious comorbidities, such as osteopenia and/or focal lytic lesions of bone, are also poorly understood. Finally, very little knowledge exists concerning the molecular events leading to benign hyperplasia and/or overt malignancy of PCs. Given that abnormal gene expression lies at the heart of most, if not all, cancers, high-throughput global gene expression profiling has become a powerful tool for investigating molecular biology and clinical behavior of diseases. Here, we discuss recent progress made in addressing many of the above issues through the molecular dissection of the transcriptome of normal PCs and MM.