Multiple myeloma patients? survival under treatment varies from a few months to more than 15 years. Clinical prognostic factors, especially beta2-microglobulin (B2M) and the international staging system (ISS), allow risk assessment to a certain extent, but do not identify patients at very high risk. As malignant plasma cells are characterized by a variety of chromosomal aberrations and changes in gene expression, a molecular characterization of CD138-purified myeloma cells by interphase fluorescence in situ hybridization (iFISH) and gene expression profiling (GEP) can be used for improved risk assessment. iFISH allows a risk stratification with presence of a translocation t(4;14) and/or deletion of 17p13 being the best documented adverse prognostic factors. A deletion of 13q14 is no longer considered to define adverse risk. Patients harbouring a t(4;14) seems to benefit from a bortezomib- or lenalidomide containing regimen, whereas patients with deletion 17p13 seem only to benefit from a high dose therapy approach using long term bortezomib (in induction and maintenance) and autologous tandem-transplantation as used in the GMMG-HD4 trial, or the total therapy 3 concept. Gene expression profiling allows the assessment of high risk scores (IFM, UAMS), remaining prognostic despite treatment with novel agents, and prognostic surrogates of biological factors (e.g. proliferation) and (prognostic) target gene expression (e.g. Aurora-kinase A). Thus, assessment of B2M and ISS-stage, iFISH, and GEP is considered extended routine diagnostics in therapy requiring multiple myeloma patients for risk assessment and, even now, to a certain extent selection of treatment.