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The ubiquitin-proteasome system is the major machinery in the cell for specific intracellular degradation. Degradation of a protein via the ubiquitin-proteasome pathway involves two successive steps: 1. Covalent attachment of multiple ubiquitin molecules to the substrate, and 2. Degradation of the tagged protein by the 26S proteasome complex. Via targeting of many substrates, the system regulates a broad array of basic cellular processes such as cell cycle, differentiation and signal transduction. Therefore, it is not surprising that aberrations in the system underlie the pathogenesis of many human diseases, among them malignancies, neurodegenerative diseases and many disorders of the immune and inflammatory response. In some pathologies the involvement of the system is direct, whereas in others the mechanistic linkage is less clear. It is expected that the ongoing extensive research in this area will shed light on the underlying pathogenetic mechanisms of the ubiquitin system-related diseases, and will lead to the development of mechanism-based therapeutic modalities.