Recently developed third generation chemotherapy programs have improved long-term disease free survival of patients with non-Hodgkin's lymphoma of aggressive histology, as compared with their predecessors. These protocols have been developed based on the cancer chemotherapy principles derived mainly of experimental tumor studies by H. Skipper and his group, and the theoretical approach by Goldie and Coldman to the occurrence of and chemotherapeutic overcoming of resistant clones. They are characterized by the use of multiple non-cross-resistant drugs in maximally elevated dose intensity. Our third generation protocol, CAMBO-VIP, has produced 90% CR and 76% DFS at 3 years. Further improvement may be obtained by application of new drugs with different mechanism of action, effective means to destruct resistant cells, and further elevation of dose intensity by myelostimmulatory cytokines or transplantation of autologous/allogeneic peripheral blood or bone marrow stem cells.