As patients with multiple myeloma (MM) have a variable clinical course, predictive markers would help determine the appropriate treatment strategy. Clinical staging is commonly used to predict outcome but, tumor marker expression and the underlying genetic changes are increasingly used to assess the biological aggressiveness of the disease. Recent studies have demonstrated the utility of immunohistochemistry (IHC) in detecting prognostic markers including: fibroblast growth factor receptor 3, cyclin D1, c-maf and p53, which have been associated with various genetic aberrations including t(4;14), t(11;14), t(14;16), and del 17p. While t(4;14), t(14;16), and del (17p) have been documented to confer a poor prognosis, t(11;14) appears neutral or even favorable factor in some studies. CD56, CD33, CD20 and CXCR4 are promising surface marker due to their roles in MM progression but further studies of larger cohorts are necessary to assess their prognostic relevance. In this review, we discuss the biological function and clinical relevance of the main prognostic markers in MM and discuss the role of IHC in the stratification of patients into appropriate risk categories.