Enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC) colonize the gut mucosa via attaching and effacing (A/E) lesions. For years cultured cells were used as model systems to study A/E lesion formation, which showed actin accumulation under attached bacteria that can be raised above the plasma membrane in a pedestal-shaped structure. Studies of prototypical strains revealed that although both converge on N-WASP EPEC and EHEC O157:H7 use different actin polymerization pathways. While EPEC use the Tir-Nck pathway, Tir(EHECO157) cooperates with TccP/EspF(U) to activate N-WASP. However, recent in vitro studies revealed a common EPEC and EHEC Tir-dependent and Nck-independent inefficient actin polymerization pathway. Unexpectedly, bacterial populations studies demonstrated that most non-O157 EHEC strains and EPEC lineage 2 strains can utilize both the Nck and TccP2 pathways in vitro. Importantly, in vivo and ex vivo mucosal infections have shown efficient A/E lesion formation independently of Nck and TccP. This review covers the progression in our understanding of EPEC and EHEC infection, through the different milestones obtained using cultured cells, to the realization that EPEC and EHEC have much more in common than previously appreciated and that mucosal attachment and microvillous effacement may be the key events, rather than pedestal formation.