While it is quite unusual for totally new types of cancer to develop, it is not unusual for new and distinct forms of cancer to be recognized among what were previously thought to be well-defined homogeneous diseases. Such is the case with mantle cell lymphoma (MCL). Originally recognized in Europe and subsequently called many different names, the unifying term MCL was proposed by an international consensus conference in 1992. Morphology alone was not sufficient to accurately separate these cases from other “small round cell” lymphomas. However, morphology plus an immunophenotype consisting of CD20 , CD22 , IgM , IgD , and CD5 , as well as either detection of the characteristic chromosomal translocation t(11;14) or overexpression of the resultant gene product cyclin D1, result in an accurate diagnosis. Furthermore, the previously unrecognized entity of MCL was not rare and actually represented 6% of all non-Hodgkin’s lymphomas. A retrospective review of 375 patients enrolled on Southwest Oncology Group (SWOG) indolent lymphoma clinical trials demonstrated that these cases did not have an indolent course: the median progression-free survival following initial treatment was only 20 months, the median survival was only 36 months, and no patients were cured of their disease. A subsequent review of 524 patients treated on 12 different clinical trials revealed amazing uniformity in the treatment results. Thus, in comparison with the indolent lymphomas, which were incurable but had a median survival of 7 to 10 years, and the aggressive lymphomas, which could be cured in 40% to 50% of all cases, patients with MCL could be viewed as havingtheworstprognosisofallformsoflymphoma.ThatmanuscriptconcludedthatpatientswithMCL“arecandidatesforinnovative (and hopefully more successful) therapy.” Clinical trials conducted in the intervening years have generally yielded disappointing results. Although there is no established standard of care for patients with MCL, combination chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) remained the most commonly used initial treatment, especially in the United States. There still remains some controversy over the value of doxorubicin. Fludarabine-based regimens are also utilized. After rituximab was shown to have an approximately 30% response rate in patients with relapsed MCL, Howard et al conducted a phase II study of CHOP plus rituximab (RCHOP) in untreated patients. Although they did note an increased complete remission rate compared with historical controls, there did not seem to be any difference in progression-free or overall survival. Hiddeman et al recently reported the initial results of a relatively small randomized trial in untreated MCL comparing CHOP and R-CHOP. Although there seemed to be some improvement in time to treatment failure from the addition of rituximab, the magnitude of the benefit was not great. The study also had a second randomization to interferon maintenance therapy or autologous stemcell transplantation; those aspects of the study have not yet been analyzed. The only published trial that reported greatly improved results in MCL was a single-institution study by The M.D. Anderson Cancer Center group, with relatively short follow-up, utilizing HyperCVAD (fractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone) with or without stem-cell transplantation. However, allogeneic transplantation is not an option for most patients with MCL because of their median age of 60 years; the vast majority of patients who undergo autologous stem-cell transplantation will relapse. Subsequently, the same group reported that the addition of rituximab to the HyperCVAD regimen eliminated the need for stem-cell transplantation. A national phase II trial of that same regimen is currently being conducted by SWOG. Thus, it is clear that new therapeutic approaches for the treatment of patients with MCL need to be developed. A series of new agents, including bortezomib, thalidomide, flavopiridol, pixantrone, m-TOR inhibitors, and others, has shown some initial activity in pretreated patients. In this issue of the Journal, O’Connor et al and Goy et al, report the results of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 4 FEBRUARY 1 2005