Among the most fundamental characteristics of a protein are the N- and C-termini defining the start and end of the polypeptide chain. While genetically encoded, protein termini isoforms are also often generated during translation, following which, termini are highly dynamic, being frequently trimmed at their ends by a large array of exopeptidases. Neo-termini can also be generated by endopeptidases after precise and limited proteolysis, termed processing. Necessary for the maturation of many proteins, processing can also occur afterwards, often resulting in dramatic functional consequences. Aberrant proteolysis can cause wide range of diseases like arthritis or cancer. Hence, proteolytic generation of pleiotrophic stable forms of proteins, the universal susceptibility of proteins to proteolysis, and its irreversibility, distinguishes proteolysis from many highly studied posttranslational modifications. Proteases are tightly interconnected in the protease web and their aberrant activity in disease can lead to diagnostic fragment profiles with characteristic protein termini. Following proteolysis, the newly formed protein termini can be further modified, a process that affects protein function and stability.