The incidence of non-Hodgkin's lymphoma (NHL) has markedly increased in the US and other westernized countries in recent years and presents a considerable clinical challenge. NHL is divided into subtypes that follow an aggressive or indolent course. Follicular lymphoma (FL), the most common indolent subtype, and mantle cell lymphoma (MCL), an aggressive subtype that accounts for approximately 5% of cases, are generally incurable. MCL has a relatively poor prognosis, with a median survival of 3–4 years. Despite improving response rates with new agents and regimens, the lack of demonstrated improvement in overall survival in many subtypes supports the development of novel approaches, such as proteasome inhibition. Bortezomib is the first proteasome inhibitor to be evaluated in human studies. It has already been approved as second-line treatment in multiple myeloma and is now under active investigation in NHL. The US FDA has granted bortezomib fast-track designation for relapsed and refractory MCL. In vitro and in vivo studies have demonstrated single-agent activity against various lymphoid tumors, and additive or synergistic effects in combination with other agents, including standard chemotherapy drugs employed in NHL. Phase 2 clinical trials indicate that bortezomib is well tolerated and active in several NHL subtypes, with response rates of 18–60% in FL and 39–56% in MCL. A number of combination trials are currently underway with a range of standard agents. Bortezomib has the potential to play a significant role throughout the NHL treatment algorithm in the future. © 2006 Wiley-Liss, Inc.