Epidermal growth factor (EGF)-like proteins comprise a group of structurally similar growth factors, which contain a conserved six-cysteine residue motif called the EGF-domain. EGF-like factors are synthesized as transmembrane precursors, which can undergo proteolytic cleavage at the cell surface to release a mature soluble ectodomain; a process often referred to as “ectodomain shedding”. Ectodomain shedding of EGF-like factors has been linked to multiple zinc-binding metalloproteases of the matrix metalloprotease (MMP) and a disintegrin and metalloprotease (ADAM) families. Shedding can be activated by a variety of pharmacological and physiological stimuli and these activation events have been linked to the enhancement of metalloprotease activity, possibly via the action of intracellular signaling modules. Once shed from the cell surface, EGF-like factors bind to a family of four cell surface receptors named ErbB-1, -2, -3 and -4. Heterodimerization or homodimerization of these receptors following ligand binding drives intracellular signal transduction cascades, which eventuate in diverse cell fates including proliferation, differentiation, migration and inhibition of apoptosis. In addition to its role in driving normal developmental processes, a wealth of evidence now exists showing that de-regulated ErbB signaling is associated with the formation of tumors in a variety of tissues and that ectodomain shedding of EGF-like factors plays a critical event in this process. Thus, knowledge of the molecular mechanisms by which EGF-like factors are shed from the cell surface and the nature of the proteases and cellular signals that govern this process is crucial to understanding ErbB receptor signaling and potentially also in the development of novel cancer therapeutics targeting the ErbB pathway. This review focuses on the structure and function of EGF-like factors, and the mechanisms that govern the shedding of these transmembrane molecules from the cell surface.