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PURPOSE The work presented throughout this thesis sought to functionally, mechanistically, and therapeutically investigate a number of top candidate gene targets and associated signalling pathways in osteosarcoma (OSA) that were originally identified using the Sleeping Beauty (SB) transposon system. Chapter 1 begins with a current overview of OSA biology, metastasis, therapeutic treatments, and mechanisms of pain. Chapter 2 focuses on how new candidate OSA genes were identified using the SB system. Subsequent chapters (3-5) are dedicated to the functional and mechanistic characterization of three top candidate genes (SEMA4C, CSF1R, and ZNF217) with the explicit goal of characterizing their biology in the context of OSA and ultimately exploiting their therapeutic potential. MAJOR FINDINGS In brief, 1) SEMA4C was found to be implicated in promoting OSA growth and metastasis. Cellular transformation associated with these cancer phenotypes could be reversed via administration of a monoclonal antibody against SEMA4C in vitro; 2) Active CSF1R was found to be involved in OSA growth and metastatic burden in part through enhanced ERK signalling which could be disrupted through small molecule CSF1R kinase blockade; 3) ZNF217 was found to accelerate OSA progression, growth, and metastasis through regulation of PI3K-AKT signalling, which could be therapeutically blocked via an AKT inhibitor.