Island isolation can cause changes in body size, cranial characteristics, and genetic variation in mammals. We use geometric morphometrics to test skull and mandible shape and size change across three species of endemic Cozumel Island rodents in order to test the “island rule” of larger size in isolated rodents. We also sequenced the D-Loop and cytochrome b region of the mitochondrial genome and tested for differences in genetic variation between island and mainland groups, as well as population structure and gene flow in order to assess the effect of island isolation on these three rodents. We found that the three species of rodents showed varying degrees of size and shape differences from island to mainland with some species varying considerably and others not at all. The genetic results were similar with some species exhibiting potential founder effects, while others showed little differentiation between the island and mainland. We conclude that evolution on islands is highly conditional on the history, community composition, and biology of the colonizing species.