Diffuse large B-cell lymphoma (DLBCL) is a biologically heterogeneous disease for which the current approach to treatment is only successful for 50% of patients. The prognostic value of various clinical and biological factors in predicting treatment outcome is discussed in this paper. A review of the English literature was performed including original articles and relevant reviews from MEDLINE that addressed the topics of DLBCL biology and potential prognostic factors. The International Prognostic Index is, to date, the most successful clinical model for predicting outcome. In addition, a rapidly expanding list of molecules has been identified by conventional and newer diagnostic methods that may be of significant prognostic value. Gene expression profiling has led to the discovery of new biological subtypes of DLBCL based on patterns of gene expression, and a host of new genes that may play important roles in this disease. Various derangements in apoptosis, cell-cycle regulation, differentiation, and signal transduction have been noted, while the host environment and immune response also appear to modify clinical outcome. Although to our knowledge, the fundamental abnormalities underlying DLBCL remain elusive, progress is being continuously made to further the understanding of the biological heterogeneity of this disease and the use of various clinical and biological variables to predict treatment outcome. The goal is to be able to identify subgroups of patients at high risk of treatment failure and develop more effective treatment based on specific biological defects that may represent new rational therapeutic targets.