The standard treatment of high-grade B cell lymphoma with RCHOP did not change yet despite the description of the biological heterogeneity. With an overall survival rate superior to 80%, patients with an IPI score 0–2 define a good prognosis group and there is no need to modify this approach if chemotherapy still remain the main tool. How can you characterize high risk aggressive B cell Lymphoma? Important progress has been made in our understanding of the biology and immunology of the group of diseases now included within DLBCL, and now there is an expanding list of active, targeted options. The integration of molecular, genetic, and metabolic imaging studies is essential for clinical trials involving the rational assembly of drugs with various mechanisms of action and immunologic properties. Several adverse factors have been described, closely related to the technology used. In a first historical approach DLBCL can be biologically isolated in GCB and non-GCB subtype with a different outcome, Double hit Myc, Bcl2 translocations, or double expressors Myc, Bcl2 are associated with a poor prognosis. Attempts have been made to elaborate a new classification that integrate next-generation sequencing. In this heterogenous high risk lymphoma, RCHOP needs to be improved. Several targeted agents have been added to RCHOP however none of these new regimens were able until now to improve the outcome in randomized study. Another approach is to detect earlier patients still not achieving a satisfactory response. The percentage of is close to 30% and reflects the heterogeneity of the disease. Detecting early failure of response can be done by incorporating an evaluation with PET scan at diagnosis with the metabolic tumour volume and after two or four cycles for the quality of response. What can we propose for this population? Salvage chemotherapy and stem cell transplantation is the most common practice. Several studies have showed an improvement of survival for the patients with pet positive after two cycles. However, half of the patients will not be eligible for transplantation due to ineffective salvage treatment, and the other half will relapse after ASCT. There is clearly a need for new drugs that improve salvage efficacy. Impressive results have been reported with CAR-T cell engineering with a high response rate in refractory patients lasting over two years at the last report. This new approach will revolutionize the treatment of lymphoma.