Is there mitogenic signaling during endocytosis or is receptor internalization mainly an attenuator of signals? Recent data indicate that the answer appears to be yes to both questions. Signal transduction occurs physiologically from the cell surface and endocytosis downregulates signaling by removing receptors from the plasma membrane. In cancer, the involvement of endocytic/sorting proteins points to dysregulation of apparently unrelated pathways, which might account for an important causative role in neoplasia.