The metalloproteases ADAM10 and ADAM17 are involved in the release of several transmembrane proteins with important roles in development and disease. Among the many functionally diverse substrates are cadherins, L-selectin, Fas ligand, TNF-alpha, EGFR ligands, Amyloid Precursor Protein (APP), Notch receptor and Notch ligands, as well as the IL6 receptor and TNF receptors. Looking at the multitude of diseases that a disregulation of ADAM-mediated shedding is associated with - such as autoimmune and cardiovascular diseases, neurodegeneration, cancer, infection and inflammation – it becomes obvious why the regulation of these proteases is such an important research field. Environmental factors are major contributors to chronic inflammatory disease development. Fish oil (FO) supplementation, for example, is well known for its cardiovascular-protective potential enhancing vascular integrity and preventing vascular inflammation. ADAM17 and ADAM10 are discussed to contribute to the pathogenesis of vascular diseases. As such, it is tempting to speculate whether FO supplementation might influence the expression and/or activity of ADAM10 and ADAM17 in the context of atherosclerosis.