Proteolytic cleavage of transmembrane proteins is an important post-translational modification that regulates the biological function of numerous transmembrane proteins. Among the 560 proteases encoded in the human genome, the metalloprotease A Disintegrin and Metalloprotease 17 (ADAM17) has gained much attention in recent years and has emerged as a central regulatory hub in inflammation, immunity and cancer development. In order to do so, ADAM17 cleaves a variety of substrates, among them the interleukin-6 receptor (IL-6R), the pro-inflammatory cytokine tumor necrosis factor α (TNFα) and most ligands of the epidermal growth factor receptor (EGFR). This review article provides an overview of the functions of ADAM17 with a special focus on its cellular regulation. It highlights the importance of ADAM17 to understand the biology of IL-6 and TNFα and their role in inflammatory diseases. Finally, the role of ADAM17 in the formation and progression of different tumor entities is discussed.