Proteases regulating inflammation are versatile enzymes, usually extracellular matrix degrading enzymes that are involved in wound healing, angiogenesis, coagulation, development, apoptosis and other physiological processes. Their dysregulation and increased expression during inflammation can have devastating consequences, promoting etiology of vascular diseases, inflammatory arthritis, cancer, and allograft rejection. In this review several proteases (ADAMTS, granzymes, plasmin, and kallikreins) with different mechanisms and substrates are described in addition to their physiological roles and contribution to inflammation and inflammatory diseases. Inhibition of proteases may therefore represent an attractive strategy for treatment and herein we describe physiological and engineered inhibitors.