Myeloperoxidase (MPO) is a mammalian heme peroxidase released by activated immune cells, which forms chemical oxidants, including hypochlorous acid (HOCl), to kill bacteria and other invading pathogens. In addition to this important role in the innate immune system, there is significant evidence from numerous chronic inflammatory pathologies for the elevated production of HOCl and associated oxidative modification of proteins and damage to host tissue. Proteins are major targets for HOCl in biological systems, owing to their abundance and the high reactivity of several amino acid side-chains with this oxidant. As such, there is significant interest in understanding the molecular mechanisms involved in HOCl-mediated protein damage and defining the consequences of these reactions. Exposure of proteins to HOCl results in a wide range of oxidative modifications and the formation of chlorinated products, which alter protein structure and enzyme activity, and impact the function of biological systems. This review describes the reactivity of HOCl with proteins, including the specific pathways involved in side-chain modification, backbone fragmentation and aggregation, and outlines examples of some of the biological consequences of these reactions, particularly in relation to the development of chronic inflammatory disease.