Cytogenetic data have established relevance for prognostication in myeloma. Also, certain chromosomal aberrations were associated with an increased risk of progression of smoldering myeloma to active disease. The impact of cytogenetic and molecular data on treatment decisions is however limited. Myeloma patients with a t(4;14) have been shown to benefit from bortezomib treatment, while thalidomide treatment has a detrimental effect in cases with del17p13. The discovery of marked intraclonal heterogeneity has influence on therapeutic concepts to treat plasma cell disease, but so far no relevance for guiding treatment in individual cases. Cereblon is the molecular target of immunomodulatory substances, and expression levels have been linked to treatment outcome under thalidomide, lenalidomide, and pomalidomide treatment. Alternative splicing has been described for cereblon, and relevance of different isoforms for drug sensitivity is currently under study. So far no reliable clinical test exists to predict for response to immunomodulatory substances.