Osteosarcoma (OS) is the most common primary malignant bone tumor, with metastatic disease responsible for most treatment failure and patient death. A better understanding of the metastatic disease state is needed to improve patient survival. The studies presented here explore a variety of questions surrounding metastatic OS. A literature search of the PubMed database was conducted to compare the prevalence of metastatic OS at diagnosis across countries. The average prevalence of metastasis at diagnosis increased as Human Development Index score (HDI) decreased, with an 18% global average. In countries with medium/low HDI, where more barriers to accessing healthcare exist, the higher prevalence of metastasis may result from treatment delay or an artificially inflated prevalence due to patients with less severe symptoms not presenting to clinic. Canine OS is a naturally occurring, spontaneous disease with more rapid disease progression and greater incidence than human OS. An understanding and utilization of studies on metastatic OS in dogs could help identify new treatment strategies to improve patient outcomes in humans and dogs. We evaluated the similarities of metastatic OS between the species by comparing risk factors for having metastatic OS at diagnosis between pet dogs from our veterinary clinic and pediatric patients in the Surveillance, Epidemiology, and End Results database. Here we build on current knowledge of canine OS by showing that primary tumors in similar anatomical locations metastasize at comparable rates in both species. A Sleeping Beauty mutagenesis screen previously conducted in our laboratory identified Slit-Robo GTPase- Activating Protein 2 (SRGAP2) as a potential suppressor of OS metastasis. SRGAP2 controls phenotypes in neurons supporting the hypothesis that it may suppress migration in the context of cancer. Although the effects of SRGAP2 in OS were not consistent across all cell lines, they tended to support this hypothesis. Additionally, expression levels of other genes in the Slit-Robo pathway were significantly altered in a subset of mouse and human OS, and SRGAP2 protein expression was lost in a subset of primary tumor samples. SRGAP2 and other axon guidance proteins likely play a role in OS metastasis, with loss of SRGAP2 contributing to a more aggressive phenotype.