Diffuse Large B Cells Lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and comprises a large number of different entities with different clinico-pathological characteristics. The role of positron emission tomography is essential during the initial staging and post treatment assessment, and potentially at early- or mid-treatment evaluation of response. First line therapy comprises immuno-chemotherapy with rituximab and different cytotoxic agents that differ for components, dosages and frequency of administration taking worldwide-recognized pre-treatment prognostic variables into account. After relapse, peripheral blood stem cells transplantation remains the only chance of cure. This review attempts to summarize the current state of our knowledge by highlighting the leads pursued to further improve current therapeutic results.