Distinctions between craniofacial and axial muscles exist from the onset of development and throughout adulthood. The masticatory muscles are a specialized group of craniofacial muscles that retain embryonic fiber properties in the adult, suggesting that the developmental origin of these muscles may govern a pattern of expression that differs from limb muscles. To determine the extent of these differences, expression profiling of total RNA isolated from the masseter and tibialis anterior (TA) muscles of adult female mice was performed, which identified transcriptional changes in unanticipated functional classes of genes in addition to those associated with fiber type. In particular, the masseters displayed a reduction of transcripts associated with contractile and cytoskeletal load-sensing and anabolic processes, and heightened expression of genes associated with stress. Correlated with these observations were a significantly smaller fiber cross-sectional area in masseters, significantly elevated load-sensing signaling (phosphorylated Focal Adhesion Kinase (FAK)), and increased apoptotic index in masseters compared to TA muscles. Based on these results, we hypothesize that masticatory muscles may have a fundamentally different strategy for muscle design, compared to axial muscles. Specifically there are small diameter fibers that have an attenuated ability to hypertrophy, but an increased propensity to undergo apoptosis. These results may provide insight into the molecular basis for specific muscle-related pathologies associated with masticatory muscles.