Abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. Although it represents a curable disease, less than half of the patients are cured with conventional chemotherapy. This highly variable outcome indicates the heterogeneous nature of the tumor, with different genetic abnormalities and responses to therapy. The International Prognostic Index (IPI) is useful in predicting the outcome of DLBCL patients. However, patients with identical IPI can still exhibit vast variabilities in survival rate, suggesting the presence of significant residual heterogeneity within each IPI category. The discovery of specific genetic alterations and the assessment of protein expression of DLBCL lead to the identification of multiple novel single molecular markers capable of predicting the outcome of DLBCL patients independent of clinical variables. The recent application of DNA microarrays and tissue array technologies allowed a better understanding of the biology of lymphoma and development of novel diagnostic tools capable of improving the current models for outcome prediction. However, much confusion exists in the literature regarding the importance of different prognostic biomarkers and their applicability in routine practice. This review summarizes the recent progresses in our understanding of prognostic biomarkers in DLBCL and discusses whether this is the right time for biomarkers-guided risk-adjusted therapy.