Diffuse large B cell lymphoma (DLBCL) is a biologically heterogeneous disease and the most common subtype of B cell non-Hodgkin's lymphoma in the USA. Even though it is a curable lymphoma in advanced stages, up to 40 % of patients eventually relapse or fail to achieve remission. Improved understanding of the biologic complexity of DLBCL reveals a diverse range of oncogenic driver mutations and signaling pathways that are essential for growth and survival of malignant cells. Since many of these signaling pathways can be targeted by small-molecule inhibitors, the therapy for DLBCL is currently undergoing a paradigm shift away from conventional chemotherapy and toward targeted agents that capitalize on an improved biologic understanding of the subsets with the highest risk of treatment failure. Participation in well-conducted and rationally designed clinical trials will be essential to realize the potential of these targeted agents and realize the goal of improving overall outcomes in the most common B cell lymphoma in the world.