Bortezomib represents the first proteasome inhibitor to have shown antitumour activity in both solid and haematological malignancies. Inhibition of the proteasome degradation machinery will result in increased apoptosis, decreased cell proliferation and reduced angiogenic cytokine production. Multiple myeloma is the prototype of cancer where bortezomib has shown marked in vitro and in vivo 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, and later in newly diagnosed multiple myeloma patients. Subsequently, Bortezomib has been used in different clinical trials in other haematologic and solid tumours. This review focuses on the proteasome inhibition exerted by bortezomib, the first proteasome inhibitor to have shown anti-cancer activity in both solid and haematologic malignancies.