Between the 1960s and 1980s, the main focus of biological research was nucleic acids and the translation of the coded information into proteins. Protein degradation was a neglected area and regarded by many as a scavenger, non-specific and end process. While it was known that proteins are turning over, the large extent and high specificity of the process--where distinct proteins have half-lives that range from a few minutes to several days--have not been appreciated. The discovery of the lysosome by Dr. Christian de Duve did not change this view significantly, as this organelle is involved mostly in the degradation of extra- and not intracellular proteins, and it was clear that lysosomal proteases, similar to those of the gastrointestinal tract, cannot be substrate specific. The discovery of the complex cascade of the ubiquitin pathway has changed this view dramatically. It is now clear that degradation of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a broad array of basic pathways during cell life and death. With the multitude of substrates targeted and processes involved, it is not surprising that aberrations in the pathway have been recently implicated in the pathogenesis of many diseases, certain malignancies and neurodegeneration among them. Degradation of a protein via the ubiquitin pathway involves two successive steps: a) conjugation of multiple ubiquitin moieties to the substrate, and b) degradation of the tagged protein by the downstream 26S proteasome complex with release of free and re-utilizable ubiquitin. Despite intensive research, the unknown still exceeds what we currently know on intracellular protein degradation and major key problems remain unsolved. Among these are the modes of specific and timed recognition of the myriad substrates of the system and the nature of the mechanisms that underlie aberrations in the system and pathogenesis of diseases.