Plaque rupture accounts for three quarters of all hearts attacks. It occurs when the tensile haemodynamic forces overwhelm the resistance of a thin and collagen-depleted fibrous cap. Such highly-inflamed plaque caps are one example of a crucial microenvironment within the plaque. The lipid core represents another microenvironment, which is also poor in collagen and contains dead or dying cells. Leaky intraplaque microvessels and the haemorrhage that results from them lead to another interesting microenvironment. The sub-intimal space is also specialised, as are areas dominated by smooth muscle cells and connective tissues. Over the past few years it has become clear that these different microenviroments are associated with distinct macrophage phenotypes that not only respond to but also play a major part in creating and maintaining these distinct areas of the plaque by secreting and expressing proteins on their surfaces. We have focussed on the metalloproteinase system because it has the potential to regulate extracellular matrix integrity, as well as the proliferation, migration and apoptosis of vascular cells. Here, we discuss evidence for the association of distinct metalloproteinase and inhibitor profiles with different plaque microenvironments and macrophage phenotypes, with emphasis on areas of pro-inflammatory activation and hypoxia. We also report results from animal experiments and human tissue biobanks that demonstrate the pathophysiological potential of metalloproteinases and the possibilities for new diagnostics and treatments based on the use of inhibitors.