Chemotherapy for cancer causes significant gut toxicity known as mucositis. The pathogenesis of mucositis is ill defined. Recent clinical research guidelines have highlighted epithelial junctional complexes as emerging targets within mucositis research. Given the robust biological evidence linking tight junctions and matrix metalloproteinases, key mediators of mucositis, tight junction proteins have received significant attention. Despite this, the link between tight junctions, matrix metalloproteinases and mucositis development is yet to be established. This critical review therefore aims to describe the role of matrix metalloproteinases in mucositis, and how matrix metalloproteinase-dependent tight junction disruption may contribute to the pathobiology of mucositis.