One of the most important negative-feedback control mechanisms for epidermal growth factor receptor (EGFR) signalling is receptor endocytosis and downregulation; mutations in EGFR that impair this process are thought to be involved in the induction of cancer. Endocytosis of EGFR is regulated by numerous post-translational modifications; however, blocking these modifications does not completely prevent EGFR endocytosis. This suggests that other mechanisms are also involved in the internalisation process. Recent studies have implicated EGFR clustering as a possible mechanism, so Paul van Bergen en Henegouwen and colleagues (p. 4900) investigated this possibility by making use of biparatopic antibody fragments from llama (VHHs). The authors show that these antibodies cluster EGFR to a similar extent to that by EGF but without stimulating tyrosine kinase activity. Using this approach, they show that clustering-induced internalisation of EGFR is clathrin mediated and requires the N-terminal GG4 dimerisation motif of the transmembrane domain (TMD) of EGFR. EGF-induced internalisation of EGFR was completely blocked by a single mutation in the TMD dimerisation motif in combination with a mutation that inactivated the kinase. Moreover, mutations in the TMD reduced EGFR degradation and eventually led to sustained signalling. This study has demonstrated a new role for the EGFR TMD dimerisation motif in clustering-induced receptor internalisation, degradation and signalling.