DLBCL (diffuse large B-cell lymphoma) is the most common subtype of non-Hodgkin's lymphoma. Current therapy for patients includes chemotherapy and monoclonal antibodies. Although oncogene-targeted therapy is dramatically successful for patients with certain kinds of leukaemias, there are no such agents yet for DLBCL. One reason for this is that several key oncogenes involved in DLBCL pathogenesis are transcription factors, which are difficult to therapeutically target with small molecules. Recent advances in the structural and functional characterization of DLBCL oncogenes have facilitated design of CPPs (cellpenetrating peptides) with potent inhibitory effects on DLBCL and other aggressive lymphomas. CPPs targeting the Bcl (B-cell lymphoma)-6, Bcl-2, Myc and NF-kappaB (nuclear factor kappaB) oncogenic pathways, among others, could improve efficacy and reduce toxicity of anti-lymphoma therapy. Another barrier towards effective therapy in DLBCL is its profound molecular heterogeneity. Combinatorial administration of oncogene-targeted CPPs based on the molecular profiles of individual patient tumours could allow individualized targeted therapy regimens to be developed.