Diffuse large B-cell lymphoma (DLBCL) is the most frequent non-Hodgkin lymphoma in western countries. Despite the addition of rituximab to chemotherapy, the prognosis is still poor and almost one-third of patients fail or relapse after first-line treatment. Gene expression profiling has identified three main signatures related to subgroups with different biological characteristics and responses to treatment. Novel agents targeting the oncogenic drivers of these subsets are currently under investigation with the aim of providing a tailored approach and avoiding unnecessary toxicity. Herein, we review the emerging therapies for DLBCL with a focus on preclinical and early clinical trials as well as future directions.