Both receptor tyrosine kinases epidermal growth factor receptors (EGFRs) and their ligands are transmembrane proteins. It has been known that ligand binding activates cytoplasmic tyrosine kinase domains of EGFRs, resulting in the transduction of signals for cell proliferation, migration, differentiation or survival. In an EGFRs-ligands system, however, signal transduction occurs not only unidirectionally but also bidirectionally, which is regulated by cell-cell contact and proteolytic cleavage. Recent studies of proteolytic cleavage 'ectodomain shedding' of EGFRs and their ligands mediated by membrane-type metalloproteinases, a disintegrin and metalloproteinases have been unveiling novel functions and molecular mechanism of their remnant peptides. In addition, the study of the remnant peptide signalling would be essential for understanding the physiological and pathological relevance of anti-shedding therapeutic strategies for diseases such as cancer.