Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) elicit proliferation, migration, and differentiation in a wide spectrum of cell types through various signal transduction pathways. These activities are attenuated by receptor internalization, intracellular trafficking through endosomes, and degradation in lysosomes, resulting in decreased receptor expression. However, there is now considerable evidence that EGFRs continue to signal in endosomes, forcing us to reevaluate the outcomes of receptor trafficking. An exciting revelation is that internalized receptors extend some signaling activities but not others, suggesting that certain responses, such as cell motility, must be mediated at the cell surface. Still, only when the effects of decreased receptor populations and signaling compartmentalization are integrated can we hope to understand and manipulate receptor function at the molecular level.