Soluble proteins play vital roles in mediating intercellular communication. Many of these proteins are secreted as freely soluble molecules, but an important class of signaling proteins are first synthesized and presented at the cell surface as transmembrane precursor proteins. Unlike classically secreted proteins, many of these molecules are regulated at an additional level, requiring proteolytic cleavage for activity. This review focuses on a subset of these proteins, which are cleaved by tumor necrosis factor alpha-converting enzyme (TACE)/ADAM17, and on their role in cancer.