Diffuse large B-cell lymphoma (DLBCL) not otherwise specified is the most common subtype of large B-cell lymphoma group, with differences in prognosis, reflecting heterogeneity in pathological, molecular, and clinical features. Current treatment standard is based on multiagent chemotherapy including anthracycline and monoclonal antiCD20 antibody, which leads to cure of 60% patients. Recent years have brought new insights to the lymphoma biology and helped to refine risk groups. Results of these studies inspired design of new clinical trials with targeted therapies and response-adapted strategies and allowed to identify groups of patients potentially benefiting from new agents. This review will summarize recent progress in identifying high-risk DLBCL patients with employment of clinical and biological prognostic factors assessed at diagnosis and during treatment in the front line setting It will also discuss new treatment strategies with the application of targeted agents and immunotherapy, including response-adapted strategies.