Several genetic mechanisms underlying the pathogenesis of multiple myeloma have been elucidated in the past decade. In particular, the presence of two distinct karyotypic patterns, that identify two patient groups and drive different pathogenetic and prognostic paths in the development of myeloma, have been identified, and the role of reciprocal chromosomal translocations and cyclin dysregulation have been identified. Despite this progress, several questions of critical importance remain to be addressed for the understanding of the pathogenesis of multiple myeloma. For example, little is known about the role of th primary events, including cyclin D overexpression and multiple myeloma set domain activity in the early pathogenesis of the disease. The additional lesions that promote the evolution of monoclonal gammopathy of undetermined significance to multiple myeloma (MM) and, within MM, the progression toward a more aggressive and proliferative disease is only starting to emerge. The heterotypic relationship between the stroma and the MM plasma cells also has not been fully explored. The understanding of the biology of MM cancer stem cells and of the pathways driving their maintenance, proliferation, and differentiation is still in its infancy. Recent and ongoing high-resolution genomic studies are leading the way toward a more refined and conclusive understanding of this disease.