Activated EGF (epidermal growth factor) receptors are removed from the cell surface via endocytosis and subsequent degradation in the lysosome. This ultimately attenuates EGF receptor signals and diminishes the level of cell activation. The mechanisms underlying the EGF receptor down-regulation are beginning to be elucidated at the molecular level. Recent reports have indicated that receptor monoubiquitination and networks of protein-protein interactions control distinct steps in EGF receptor internalization, endosomal trafficking and sorting for lysosomal degradation. The emerging importance of the ubiquitin ligase Cbl and the adaptor molecule CIN85 (Cbl-interacting protein of 85 kDa) in the regulation of these pathways is discussed in detail.