The metalloprotease ADAM17 is a key regulator of the TNF, IL-6R and EGFR signaling pathways. The maturation and function of ADAM17 is controlled by the seven-membrane-spanning proteins iRhoms1 and 2. The functional properties of ADAM17/iRhom1 and ADAM17/iRhom2 differ in that stimulated shedding of most ADAM17 substrates tested to date can be supported by iRhom2, whereas iRhom1 can only support stimulated shedding of very few ADAM17 substrates, such as TGFα. The first transmembrane domain (TMD1) of iRhom2 and the sole TMD of ADAM17 are important for the stimulated shedding of ADAM17 substrates by iRhom2. However, little is currently known about the how the iRhoms interact with different substrates to control their stimulated shedding by ADAM17. To provide new insights into this topic, we tested how various chimeras between iRhom1 and iRhom2 affect the stimulated processing of the EGFR-ligands TGFα (iRhom1 or 2-dependent) and EREG (iRhom2-selective) by ADAM17. We designed iRhom1/2 chimeras and mutants which uncovered an important role of TMD7 of the iRhoms in determining their substrate selectivity. Computational methods utilized to characterize the iRhom1/2/substrate interactions suggest that the substrate selectivity is determined at least in party by a distinct accessibility of the substrate cleavage site to stimulated ADAM17. Moreover, chimeras between different EGFR ligand substrates indicated that all substrate domains except the cytoplasmic tail are involved in their selective shedding by iRhom1 versus iRhom2. These studies not only provide new insights into why the substrate selectivity of stimulated iRhom2/ADAM17 differs from that of iRhom1/ADAM17, but also suggest new approaches for targeting the release of specific ADAM17 substrates.