Proteasome inhibitors and immunomodulatory drugs (IMiDs) have demonstrated clinical potential as novel therapies for non-Hodgkin lymphoma (NHL). Bortezomib, a peptide aldehyde derivative that inhibits the proteasome by binding directly to its active sites, is the most extensively studied agent in the clinical setting. Single-agent bortezomib is effective in several lymphoid malignancies, and is recommended for second-line treatment of mantle-cell lymphoma (MCL). Ongoing trials are investigating the combination of bortezomib with chemotherapy, and with agents that target Bcl-2 proteins. Although proteasome inhibitors are potentially potent anti-tumor drugs, the pleotropic nature of their biological effects means that further research is required to elucidate the optimal combinations, doses and schedules. In addition to proteasome inhibitors, the IMiDs, such as lenalidomide, have the potential to improve outcomes for patients with NHL. These drugs inhibit cell growth and proliferation by several mechanisms, including blocking the effect of growth factors and stimulating T cells and natural killer cells. Lenalidomide is particularly effective in lymphoproliferative disorders such as multiple myeloma, and is active in patients with various forms of NHL, with a favourable side-effect profile. Complimentary clinical and pharmacological features suggest that lenalidomide may be effective when combined with monoclonal antibodies. Ongoing and future studies will provide further information.