Diffuse large B-cell lymphoma (DLBCL) responds well to treatment with CHOP and the R-CHOP regimen, but a subset of patients still fail to achieve complete or durable responses. Recent advances in gene expression profiling have led to the identification of three different subtypes of DLBCL, and confirmed that patients with the activated B-cell (ABC) disease subtype are less likely to respond well to CHOP-based regimens than those with germinal centre B-cell-type (GCB) disease. This discovery could herald the use of gene expression profiling to aid treatment decisions in DLBCL, and help identify the most effective management strategies for patients. Treatment options for patients with relapsed or refractory DLBCL are limited and several novel agents are being developed to address this unmet clinical need. Novel agents developed to treat plasma cell disorders such as multiple myeloma have shown promising activity in patients with NHL. Indeed, the immunomodulatory agent lenalidomide and the proteasome inhibitors bortezomib and carfilzomib, as single agents or in combination with chemotherapy, have already demonstrated promising activity in patients with the ABC subtype of DLBCL. One should not be complacent however when applying these agents to new disease types, because dose and drug scheduling can have marked effects on the responses achieved with investigational agents. As more targeted agents are developed, the timing of administration with other agents in clinical trials will become increasingly important to ensure maximal efficacy while minimizing side effects.