ADAM metalloproteases are membrane bound glycoproteins that control many biological processes during development and differentiation, mainly by acting as ectodomain sheddases. The Drosophila genome contains five genes that code for classical ADAM proteins which are characterized by a highly conserved domain structure with the respective catalytic domains facing the extracellular space. More than 50 genes encode related proteins such as those that have lost their primary enzymatic activity while retaining, e.g., their adhesive properties. The physiological relevance of many Drosophila ADAMs and their relatives is still unknown, however for others, a striking role during organogenesis and tissue maintenance has been demonstrated during the last few years. We have carried out genetic screenings combined with candidate approaches, aiming to identify new components involved in cardiogenesis and muscle differentiation. Herein we summarize our results with a particular focus on metalloproteases with known or potential roles in tissue differentiation.