Among the ∼80 ADAM17 substrates identified so far (3), the protease has shown to be especially important for cleavage of many regulators involved in immune and inflammatory responses as well as cancer development, including membrane-tethered pro–TNF-α, both TNF-α receptors (TNFRI and TNFRII), IL-6R, ligands of the EGF-R (e.g., TGF-α and amphiregulin), and adhesion molecules (e.g., L-selectin and ICAM-1) (3, 6). The gene discussed is TNF; the disease is cancer.