The approach we have followed in developing treatment strategies for lymphoma consists of testing new combinations in patients with recurrent disease and, if these are found to be effective, advancing them to front-line therapy. Three series of salvage regimens tested at the M. D. Anderson Cancer Center (MDACC) will be described. These were initially based on ifosfamide/etoposide, later on high-dose cytarabine/cisplatin, and more recently on a novel strategy that first uses MINE (mesna/ifosfamide/Novantrone [mitoxantrone; Lederle International, Wayne, NJ]/etoposide) for induction of remission and, following the attainment of the maximum response to MINE, changes treatment to a non--cross-resistant combination known as ESHAP (etoposide/Solu-medrol ([methylprednisolone]/high-dose cytarabine/cisplatin). The front-line management of intermediate-grade lymphoma at MDACC currently is based on prognostic factors. The criteria for selecting categories of less favorable patients will be discussed. A new regimen, alternating triple therapy based on three non--cross-resistant drug regimens, currently is being explored for these patients. Already this regimen has shown an early advantage in the worst category of cases, those with M.D. Anderson stage D (high tumor burden, high levels of lactate dehydrogenase). The data, however, remain preliminary.