Mammalian proteases segregate into several distinct protein families that employ different functional domains to hydrolyze peptides bonds with different specificities and affinities. These enzymes play central roles in critical cellular and systemic processes, including regulation of cell growth, differentiation, homeostasis, and apoptosis; and cancer initiation, progression, and metastasis. Human proteases segregate into five distinct catalytic classes; the metalloprotease, serine protease, and cysteine protease families have the most members, while the aspartic and threonine peptidase families have relatively few examples. Section 1 discusses the five different types of human proteases and summarizes some of their known functions during tumorigenesis, migration, and metastasis. Section 2 focuses on how cancer degradomes, defined as all the proteases, protease inhibitors, and protease substrates regulated by a given cancer, affect cancer promotion and suppression, and current approaches for degradome profiling. Protein degradation products generated during cancer progression, invasion, and metastasis alter the tumor microenvironment to influence these processes. These cancer-associated protein degradation profiles (aka tumor peptidomes) represent a potentially rich pool of candidates for cancer biomarker discovery. Section 3 focuses on the benefits and challenges associated with peptidome studies, and methods employed to conduct them. Section 4 discusses recent studies that use circulating peptides as cancer biomarkers, and how the abundance of peptides reflects the activity of their source proteases during cancer progression. We hope this chapter will convey a good sense of current research on how cancer-associated proteases, degradomes, and their resulting peptidomes can improve our knowledge of cancer biology, improve diagnosis and evaluation, and inspire new ideas in this and related research areas.