Proteolytic enzymes play an essential role in many biological and pathological processes. Taking advantage of the recent availability of several mammalian genome sequences and by using a set of computational approaches, we have annotated and compared the degradome or complete repertoire of proteases of different mammalian species including human, mouse, rat, and chimpanzee. These studies have allowed us to expand our knowledge about the complexity, evolution, and diversity of proteolytic systems, which represent about 2% of the studied genomes. In this chapter, we review the genomic and computational methodologies used in this degradomic analysis and summarize the main findings derived from comparison of mammalian degradomes.