The canine genome has been influenced by domestication of the gray wolf, environmental factors, and led to creation of approximately 400 modern breeds of domestic dog (Canis familiaris) over approximately 15,000 years. This evolution represents that greatest genetic experiment ever conducted. Most modern breeds have a short evolutionary history that may only be about 100 generations. Breed creation has led to concentration of disease-causing genetic variants in specific breeds, many of which model the equivalent disease in human beings. The genomes of modern purebred dogs are a mosaic consisting of small regions associated with domestication and longer regions underlying recent breed creation. This genomic architecture facilitates dissection of the genetic contribution to disease phenotypes. Genome-wide association study (GWAS) within a breed segregating for a trait can easily identify the genomic region(s) underlying the trait because of long-range linkage disequilibrium, although such regions may be several megabases long and contain many genes. Subsequent fine-mapping of associated loci across breeds or use of whole-genome sequencing can identify specific candidate causal variants. We have undertaken a within-breed GWAS of anterior cruciate ligament (ACL) rupture in the Labrador Retriever breed, a breed with a high prevalence of ACL rupture (5.79%). Our findings suggest that ACL rupture is: 1) Moderately heritable; 2) Highly polygenic; and 3) A disease in which genetic loci have small and moderate additive effects on ACL rupture. These observations suggest that prediction of disease risk will need to use whole genome regression methods.