The overall therapeutic strategy for the management of lymphomas at the M.D. Anderson Cancer Center consists of devising new drug combinations that are tested first in patients with relapsed lymphoma and, if successful, are then incorporated into first-line management. This article describes the preliminary results of the alternating triple therapy (ATT) first-line regimen for patients with M.D. Anderson stages B, C, and D of intermediate-grade lymphomas. This regimen is based on three non-cross-resistant combinations, two of which were originally developed as salvage therapy. Statistically significant improvement in the overall survival and failure-free survival at 1 year has already been seen for the stage D patients (high tumor burden and high lactate dehydrogenase levels). A new therapeutic strategy in current use for patients with Ann Arbor stages III and IV low-grade lymphoma is also described. This regimen consists of CHOP-Bleo (cyclophosphamide, doxorubicin, vincristine, prednisone-bleomycin) alternating with ESHAP (etoposide, Solu-medrol [methylprednisolone, Upjohn Company], Ara-C [cytarabine], platinum) and NOPP (Novantrone [mitoxantrone, American Cyanamid Company], Oncovin [vincristine Eli Lilly and Company], procarbazine, prednisone). Maintenance interferon (IFN) is also used for 1 year. Finally, the current salvage regimen in use at the M.D. Anderson Cancer Center is described. This MINE-ESHAP regimen consists of an induction with mesna, ifosfamide, Novantrone (mitoxantrone), and etoposide, which is administered until maximum response and followed by consolidation with 3 to 6 courses of ESHAP. The preliminary results of this regimen are encouraging, but more follow-up is required before any conclusions can be drawn.