The number, size and shape of mammalian teeth vary widely – just compare a person's smile with a dog's ‘smile’. But what controls the patterning of dentition? Mutations in Wise (Sostdc1), which encodes an inhibitor of Lrp5- and Lrp6-dependent Wnt signalling, cause patterning defects in tooth development in mice. Now, by investigating the pathways modulated by Wise, Robb Krumlauf and co-workers show that crosstalk between Wnt and other signalling pathways controls mouse tooth development (see p. 3221). The researchers use genetic experiments to reveal that Wise suppresses the survival of vestigial tooth buds in the normally toothless region between the incisors and molars by inhibiting Lrp5- and Lrp6-dependent Wnt signalling. They also identify the Fgf and Shh signalling pathways as major downstream targets of Wise-regulated Wnt signalling, and show that Shh acts as a negative-feedback regulator of Wnt signalling. Thus, the researchers suggest, variations in the expression of signalling modulators such as Wise could underlie the evolutionary diversity in mammalian dentition.