In the study presented, we analyzed the expression of ADAM10 and ADAM7 and their regulating miRNAs in RB cell lines and patient tumors and set out to unravel the effects of a lentiviral ADAM10 and ADAM17 single and double knockdown on RB cell viability, proliferation, apoptosis, anchorage-independent growth and AKT phosphorylation in vitro as well as tumor formation capacity, invasiveness, and dissemination in vivo. Here, ADAM10 is linked to retinoblastoma.