Most reptiles and fish have multiple sets of teeth during their lifetime. However, most mammals have only one set of replacement teeth and some mammals, like mice, have only a single set with no replacement. Now, Abigail Tucker and colleagues pinpoint why mice don’t have replacement teeth by comparing gene expression in the dental lamina of the mouse and the minipig, which has two sets of teeth. Wnt signalling is known to be required for tooth replacement in other vertebrates; the authors now show that Wnt activity is absent in the rudimentary successional dental lamina (RSDL) in mice. Using sophisticated genetic techniques, the researchers activate Wnt signalling in the mouse RSDL at E15.5 and E16 stages of development, and ectopic teeth are formed as a consequence. These results demonstrate the potential of the RSDL as a source for replacement teeth in mice, and provide an experimental system suitable for studying the mechanisms behind replacement. In addition, the authors identify a negative-feedback loop between Wnt and Sox2 that controls formation of replacement teeth. Finally, they report that culturing the RSDL in isolation revitalised its tooth-forming potential, suggesting that the first generation of teeth might prevent replacement teeth from developing. These results provide a conceptual advancement in the tooth-replacement field, as well as providing new insights into how traits are lost during mammalian evolution and how they might be restored.