Mantle cell lymphoma (MCL) is one of the most challenging lymphomas to treat. In the first-line setting, high-dose therapy (HDT) and autologous stem cell transplantation or hyperCVAD/rituximab suggest benefit, especially in patients aged < 60 years. Nucleoside analogue-based regimens represent an alternate option in patients ineligible for HDT. Fludarabine in combination with cyclophosphamide or mitoxantrone has shown activity, and the results were superior with the addition of rituximab. Other cytotoxic agents, such as cladribine, clofarabine, or bendamustin, showed promising activity as well. A variety of new monoclonal antibody (MoAb) agents, such as humanized anti-CD20, alemtuzumab, anti-HLA-DR, anti-CD22 (as an immunotoxin carrier), anti-CD40, as well as MoAb-targeting TRAIL-R1 and TRAIL-R2 are being tested. Radioimmunotherapy with Yttrium 90-ibritumomab tiuxetan and Iodine 131 tositumomab have been tested alone or in combination with chemotherapy, including as part of HDT and autologous stem cell transplantation, in which they showed the best results. New vaccine modalities are exploring the use of tumor cell-based vaccines or of agents that block or activate costimulatory pathways/molecules, such as CTLA-4-Ig. Allogenic transplantation represents a potential curative option for MCL, especially nonmyeloablative transplantation, more feasible in that population. A plethora of novel biologic agents have surfaced, such as bortezomib, temsirolimus, thalidomide, lenalidomide, MoAb anti-vascular endothelial growth factor or vascular endothelial growth factor-Trap, and flavopiridol. Other targets include gene transcription through histone regulation; nuclear factor-ķB pathway; protein kinase C inhibitors; small-molecules targeting apoptosis, such as antisense Bcl-2, pan-Bcl-2 family member inhibitors; MoAb agonists of cell death receptors; caspases regulators (inhibitors of apoptosis proteins, survivin); and MDM2 antagonist regulators of p53. A molecular approach to define biomarkers might help identify subgroups of patients and help develop rational therapies.