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The acquisition of masticatory capability by mammals allowed a better processing of food and a consequent increase in the efficiency of nutrients intake by the digestive system. The development of tooth classes and variations in tooth number can be considered intrinsic characteristics of mammalian dentition. These features allowed species to develop specialized dentitions, creating new adaptive zones. Comparative developmental data from knockout mutant mice and human tooth agenesis present new insights on the molecular strategies that permitted rapid phenotypic differentiation, adaptation and speciation of mammalian dentition.