Multiple myeloma (MM) is a tumor of mature, isotype switched plasma cells. It is a uniformly fatal malignancy that is frequently preceded by a common (1% of adults), benign pre-clinical phase, monoclonal gammopathy of undetermined significance (MGUS). I am focused on understanding the molecular events that lead to the development of MGUS, and to its progression to MM. We have determined that MM is characterized by recurrent chromosome translocations to the immunoglobulin heavy chain gene on 14q32. We have cloned over 35 translocation breakpoints, and identified five frequent translocation partners, that are present in almost one half of patients with MM. One fifth of patients have t(11;14)(q13;q32) or t(6;14)(p21;q32) with dysregulation of cyclin D1 or D3 respectively. Fifteen percent of patients have t(4;14)(p16;q32) with dysregulation of FGFR3 and MMSET. Finally about 10% of patients have t(14;16)(q32;q23) or t(14;20)(q32;q11) with dysregulation of the maf family basic zipper transcription factors c-maf and mafB, The patients lacking one of these translocations have ectopic expression of cyclin D1 and frequent hyperdiploidy with trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19, 21. Direct or indirect dysregulation of a D-type cyclin appears to be 4 unifying event in the pathogenesis of almost all patients with multiple myeloma.