While the role of ADAM17 and its specific substrates (e.g., EGFR ligands, Notch, sIL-6R) has been previously documented in several cancers (e.g., lung cancer, CRC, pancreatic cancer, breast cancer) [29,41,42,43,61,97,132,177,182,187,194,195,196,197], for the purpose of this review, we will focus on lung cancer, for which many mechanistic insights are relevant to other cancer types. The gene discussed is EGFR; the disease is lung cancer.