Hepatocyte growth factor (HGF; also known as scatter factor) induces epithelial cell scattering, a process that involves the loss of cell-to-cell junctions and the acquisition of motile and invasive mesenchymal features by epithelial cells, and underlies HGF-induced invasive growth in several human tumours. Now, on page 4853, Chia-Che Chang and colleagues propose that Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor involved in cell proliferation, differentiation and self-renewal, mediates the effect of HGF on cell scattering. The authors show that HGF upregulates KLF4 expression and induces scattering in HepG2 hepatocellular and MDCK epithelial cells through activation of the mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase (MEK/ERK) pathway and induction of early growth response protein 1 (EGR1). By contrast, knockdown of KLF4 in these cell lines inhibits HGF-induced E-cadherin expression and cell scattering. EGR1 binds directly to the KLF4 promoter to induce KLF4 transcription, report the authors. Moreover, EGR1-induced KLF4 binds to the KLF4 promoter in order to create a positive feedback loop that sustains KLF4 expression and cell scattering. These findings provide new insights into the molecular mechanisms underlying cancer progression and might facilitate the development of cancer therapies that target this crucial process.