Thirty years ago, most biochemical and molecular science concerned what went on inside cells. Hence, release of enzymes into the extracellular space was seen as important only for specialised functions, such as digestion of nutrients or in blood clotting, events that took place outside solid tissues. Moreover, the discovery of ecto-enzymes–enzymes with their active sites pointing to the extracellular space–was viewed first with scepticism and then largely as a curiosity. Appreciating the full importance of pericellular metabolism for embryogenesis, morphogenesis and cellular regulation needed a revolution in thinking catalysed in significant part by the seminal discovery that resorption of the tadpole tail during metamorphosis depended on the production of a collagenase [1]. This enzyme we now designate matrix metalloproteinase 1 (MMP-1) in recognition that it was the first secreted member of a family of enzymes that requires a Zn2+ ion at the active site. Later on, the first ecto-MMP (membrane type-1 MMP, MMP-14) was discovered [2]. Nagase et al. [3] overview the more than 20 secreted and at least 6 membrane-type MMPs, many of which are present in the cardiovascular system. Their substrates include the major structural matrix components, collagens, elastin, proteoglycan core proteins and glycoproteins, as well as many non-matrix proteins. Disintegin metalloproteinases (ADAMs) also share the MMP catalytic domain; Manso et al. review their emerging functions in the cardiovascular system [4]. Other groups of extracellular neutral proteases with thiol or serine groups at their active sites synergise with the MMPs, in part by activating MMP proforms [3]. This raises the questions why there is such a rich landscape of extracellular proteases and whether any individual enzymes play an indispensable role in cardiovascular function or disease. Janssens and Lijnen [5] summarise how the power of genetic modification in mice has begun to provide answers, the original study by Wang et al. [6] being a specific example.