Molar size in Mammals shows considerable disparity and exhibits variation similar to that predicted by the Inhibitory Cascade model. The importance of such developmental systems in favoring evolutionary trajectories is also underlined by the fact that this model can predict macroevolutionary patterns. Using backcross mice, we mapped QTL for molar sizes controlling for their sequential development. Genetic controls for upper and lower molars appear somewhat similar, and regions containing genes implied in dental defects drive this variation. We mapped three relationship QTLs (rQTL) modifying the control of the mesial molars on the focal third molar. These regions overlap Shh, Sostdc1 and Fst genes, which have pervasive roles in development and should be buffered against new variation. It has theoretically been shown that rQTL produces new variation channeled in the direction of adaptive changes. Our results provide evidence that evolutionary/disease patterns of tooth size variation could result from such a non-random generating process.