The shape of the cranial vault, a region comprising interlocking flat bones surrounding the cerebral cortex, varies considerably in humans. Strongly influenced by brain size and shape, cranial vault morphology has both clinical and evolutionary relevance. However, little is known about the genetic basis of normal vault shape in humans. We performed a genome-wide association study (GWAS) on three vault measures (maximum cranial width [MCW], maximum cranial length [MCL], and cephalic index [CI]) in a sample of 4419 healthy individuals of European ancestry. All measures were adjusted by sex, age, and body size, then tested for association with genetic variants spanning the genome. GWAS results for the two cohorts were combined via meta-analysis. Significant associations were observed at two loci: 15p11.2 (lead SNP rs2924767, p = 2.107 × 10-8) for MCW and 17q11.2 (lead SNP rs72841279, p = 5.29 × 10-9) for MCL. Additionally, 32 suggestive loci (p < 5x10-6) were observed. Several candidate genes were located in these loci, such as NLK, MEF2A, SOX9 and SOX11. Genome-wide linkage analysis of cranial vault shape in mice (N = 433) was performed to follow-up the associated candidate loci identified in the human GWAS. Two loci, 17q11.2 (c11.loc44 in mice) and 17q25.1 (c11.loc74 in mice), associated with cranial vault size in humans, were also linked with cranial vault size in mice (LOD scores: 3.37 and 3.79 respectively). These results provide further insight into genetic pathways and mechanisms underlying normal variation in human craniofacial morphology.