Within a group of organisms, some morphologies are more readily generated than others due to internal developmental constraints. Such constraints can channel evolutionary changes into directions corresponding to the greatest intraspecific variation. Long term evolutionary outputs, however, depend on the stability of these intraspecific patterns of variation over time and from the interplay between internal constraints and selective regimes. To address these questions, the relationship between the structure of phenotypic variance covariance matrices and direction of morphological evolution was investigated using teeth of fossil rodents. One lineage considered here leads to Stephanomys, a highly specialized genus characterized by a dental pattern supposedly favoring grass eating. Stephanomys evolved in the context of directional selection related to the climatic trend of global cooling causing an increasing proportion of grasslands in southwestern Europe. The initial divergence (up to ∼6.5 mya) was channeled along the direction of greatest intraspecific variation, whereas after 6.5 mya, morphological evolution departed from the direction favored by internal constraints. This departure from the “lines of least resistance” was likely the consequence of an environmental degradation causing a selective gradient strong enough to overwhelm the constraints to phenotypic evolution. However, in a context of stabilizing selection, these constraints actually channel evolution, as exemplified by the lineage of Apodemus. This lineage retained a primitive diet and dental pattern over the last 10 myr. Limited morphological changes occurred nevertheless in accordance with the main patterns of intraspecific variation. The importance of these lines of least resistance directing long-term morphological evolution may explain parallel evolution of some dental patterns in murine evolution.