In recent years, we have seen an explosion in knowledge of the genetics and cytogenetics of the plasma-cell neoplasms. This chapter will deal with these advances and will place them in the integrative context of the pathophysiologic basis of the disease, and will discuss the important clinical implications of these abnormalities. We have learned that myeloma can be classified into increasingly definable subgroups that follow a basic global hierarchical grouping. All gene expression profiling strategies have come to similar conclusions and confirm the subgroups previously identified by karyotype, molecular cytogenetics and other genetic studies. At the top level there are two major pathogenetic pathways for the development of plasma cell tumors: one that is associated with hyperdiploidy and one that is characterized by the presence of chromosome translocations involving the immunoglobulin heavy chain locus (IgH). These translocations are seen in up to 60% of patients, but involve a common recurrent chromosome partner in only 40-50% of patients. Several genetic markers are now shown to be associated with a shortened survival. Of these, the most common ones include abnormalities (deletion and monosomy) of chromosome 13, the global state of hypodiploidy and abnormalities of chromosome 1. Many of the translocations observed in MM are also seen in monoclonal gammopathy of undetermined significance (MGUS), even in individuals without progression to full malignant disease for many years. The identification of critical genetic lesions will pave the way for the development of disease-targeted therapy.