Alpha-macroglobulins are ancient proteins that include monomeric, dimeric, and tetrameric family members. In humans, and many other mammals, the predominant alpha-macroglobulin is alpha-2-macroglobulin (α2M), a tetrameric protein that is constitutively abundant in biological fluids (e.g., blood plasma, cerebral spinal fluid, synovial fluid, ocular fluid, and interstitial fluid). α2M is best known for its remarkable ability to inhibit a broad spectrum of proteases, but the full gamut of its activities affects diverse biological processes. For example, α2M can stabilise and facilitate the clearance of the Alzheimer’s disease-associated amyloid beta (Aβ) peptide. Additionally, α2M can influence the signalling of cytokines and growth factors including neurotrophins. The results of several studies support the idea that the functions of α2M are uniquely regulated by hypochlorite, an oxidant that is generated during inflammation, which induces the native α2M tetramer to dissociate into dimers. This review will discuss the evidence for hypochlorite-induced regulation of α2M and the possible implications of this in neuroinflammation and neurodegeneration.