Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells characterized by complex genetic aberrations and heterogeneous outcomes. Over the past 25 years, cytogenetic analysis has played a key role in the diagnosis and management of MM. This article reviews the conventional cytogenetics, molecular cytogenetics, and genomic diagnostics of MM and highlights a few recent clinical trials that demonstrate the impact of genetic risk stratification on the treatment of this plasma cell malignancy.