Gene expression profiling has had a major impact on our understanding of the biology and heterogeneity of diffuse large B-cell lymphoma. Using this technology, biological subgroups of DLBCL can be identified that have unique targets for rational therapeutic intervention. This review summarizes these potential targets, and updates the progress of clinical development of exciting novel agents for the treatment of diffuse large B-cell lymphoma. Based upon these ongoing studies, it is likely that in the near future, we will utilize gene expression profiling, or an accurate surrogate, to define the best therapeutic approach for an individual patient with DLBCL.