A disintegrin and metalloproteinase 17 (ADAM17), also known as tumor necrosis factor-α converting enzyme (TACE), is a membrane-bound enzyme that cleaves cell surface proteins, such as cytokines (e.g. TNFα), cytokine receptors (e.g. IL-6R and TNF-R), ligands of ErbB (e.g. TGFα and amphiregulin) and adhesion proteins (e.g. L-selectin and ICAM-1). Here we examine how ectodomain shedding of these molecules can alter their biology and impact on immune and inflammatory responses and cancer development. Gene targeting of Adam17 is embryonic lethal, highlighting the importance of ectodomain shedding during development. Tissue-specific deletion, or hypomorphic knock-in, of Adam17 demonstrates an in vivo role for ADAM17 in controlling inflammation and tissue regeneration. The potential of ADAM17 as therapeutic target is also discussed.