Since its recognition as a separate subtype of non-Hodgkin lymphoma (NHL) in 1994, mantle cell lymphoma (MCL) has been a very active field of clinical research due to its typical poor outcome. Besides a small subset of patients who can enjoy long-term disease-frees urvival through non-myeloablative allogenic stem cell transplant, most patients relapse and become frequently over time chemoresistant to conventional or high-dose cytotoxic-based therapy. Thankfully a number of novel agents have shown activity in MCL, most of which target distinct newly identified pathways. Proteasome inhibitors represent the first novel biological agent with promising activity in MCL with bortezomib as first in class and firstnovel agent FDA approved in relapsed/refractory MCL. Pre-clinical studies showing impressive additive or synergistic effects with other cytotoxics or biologicals, provide a rationale for a number of ongoing studies looking at combination with conventional regimens used in MCL either with chemoimmunotherapy or as consolidation or maintenance approaches post-induction. The progress in understanding MCL biology especially regarding the heterogeneity of the disease as well as emerging predictive biomarkers (both for conventional and novel therapies), will help stratify patients and refine our management to hopefully continue to improve patients' outcome.