The outcome of patients with diffuse large B cell lymphoma (DLBCL) has completely changed with the introduction of rituximab in combination with chemotherapy. This was the first targeted therapy, and it led the way to new antibodies targeting cell surface receptors and to small molecules targeting one or several key proteins of the cellular machinery. Those new therapeutic small molecules are targeting the different pathways of apoptosis, proteasome inhibitors, immunomodulators, histone deacetylase inhibitors, mammalian target of rapamycin inhibitors, heat shock protein inhibitors, PKC inhibitors, antiangiogenic agents, Syk inhibitors, and farnesyl transferase inhibitors. The new monoclonal antibodies target CD20, CD22, CD19, CD40, CD74, and HLA Drbeta. Although the majority of them have been studied in mixed subtypes of B cell lymphoma, the aim of this review was to present major results in clinical studies for these new agents in DLBCL patients, and for those that have just entered clinical evaluation, the results of pre-clinical studies in DLBCL lines.