Melatonin has been widely studied for its role in photoperiodism in seasonal breeders; it is also a potent antioxidant. Ubiquitin, a protein also widespread in living cells, contributes to many cellular events, although the most well known is that of tagging proteins for destruction by the proteasome. Herein, we suggest a model in which melatonin interacts with the ubiquitin-proteasome system to regulate a variety of seemingly unrelated processes. Ubiquitin, for example, is a major regulator of central activity of thyroid hormone type 2 deiodinase; the subsequent regulation of T3 may be central to the melatonin-induced changes in seasonal reproduction and seasonal changes in metabolism. Both melatonin and ubiquitin also have important roles in protecting cells from oxidative stress. We discuss the interaction of melatonin and the ubiquitin-proteasome system in oxidative stress through regulation of the ubiquitin-activating enzyme, E1. Previous reports have shown that glutathiolation of this enzyme protects proteins from unnecessary degradation. In addition, evidence is discussed concerning the interaction of ubiquitin and melatonin in activation of the transcription factor NF-κB as well as modulating cellular levels of numerous signal transducing factors including the tumor suppressor, p53. Some of the actions of melatonin on the regulatory particle of the proteasome appear to be related to its inhibition of the calcium-dependent calmodulin kinase II, an enzyme which reportedly copurifies with proteasomes. Many of the actions of melatonin on signal transduction are similar to those of a proteasome inhibitor. While these actions of melatonin could be explained by a direct inhibitory action on the catalytic core particle of the proteasome, this has not been experimentally verified. If our hypothesis of melatonin as a general inhibitor of the ubiquitin-proteasome system is confirmed, it is predicted that more examples of this interaction will be demonstrated in a variety of tissues in which ubiquitin and melatonin co-exist. Furthermore, the hypothesis of melatonin as an inhibitor of the ubiquitin-proteasome system will be a very useful model for clinical testing of melatonin.