Bortezomib (Velcade, formerly PS-341) represents the first proteasome inhibitor to have shown anti-tumor activity in both solid and haematological malignancies. It blocks activation of nuclear factor-kappa B (NF-kB), resulting in increased apoptosis, decreased angiogenic cytokine production, and inhibition of tumor cell adhesion to stroma. Additional mechanisms of action include c-Jun N-terminal kinase activation, effects on growth factor expression and anti-angiogenic properties. Multiple myeloma is the prototype of cancer where bortezomib has shown marked in vitro activity, which was followed by rapid translation to phase I, II and III clinical trials, and resulted in accelerated approval by the FDA for the treatment of patients with relapsed refractory disease. Different clinical trials are currently ongoing in multiple myeloma as well as in many others haematologic and solid tumors (mantle cell and follicular non-Hodgkin's lymphoma; peripheral T-cell lymphoma; Waldenström's macroglobulinemia, chronic lymphocytic leukemia; head and neck / gastroesophageal junction / stomach /colo-rectal / prostate / non-small cell lung cancer). This reviews focuses on the proteasome inhibition exerted by bortezomib, the first proteasome inhibitor to have shown anti-cancer activity in both solid and haematologic malignancies.