Proteasome inhibitors and melatonin are both intimately involved in the regulation of major signal transduction proteins including p53, cyclin p27, transcription factor NF-κB, apoptotic factors Bax and Bim, caspase 3, caspase 9, anti-apoptotic factor Bcl-2, TRAIL, NRF2 and transcription factor beta-catenin. The fact that these factors are shared targets of the proteasome inhibitor bortezomib and melatonin suggests the working hypothesis that melatonin is a proteasome inhibitor. Supporting this hypothesis is the fact that melatonin shares with bortezomib a selective pro-apoptotic action in cancer cells. Furthermore, both bortezomib and melatonin increase the sensitivity of human glioma cells to TRAIL-induced apoptosis. Direct evidence for melatonin inhibition of the proteasome was recently found in human renal cancer cells. We raise the issue whether melatonin should be investigated in combination with proteasome inhibitors to reduce toxicity, to reduce drug resistance, and to enhance efficacy. This may be particularly valid for hematological malignancies in which proteasome inhibitors have been shown to be useful. Further studies are necessary to determine whether the actions of melatonin on cellular signaling pathways are due to a direct inhibitory effect on the catalytic core of the proteasome, due to an inhibitory action on the regulatory particle of the proteasome, or due to an indirect effect of melatonin on phosphorylation of signal transducing factors.