Primary bone cancers are rare malignant diseases with significant morbidity and mortality. The treatment regimen relies on a combination of surgery (often involving amputation), chemotherapy and radiotherapy with outcomes dependent on localization of the tumour, grade, size and response to chemotherapy. Both treatment options and survival statistics have remained constant over the past 40 years and alternative therapies need to be explored. Purinergic signalling involving the interaction of extracellular nucleotides with P2 receptors has been investigated in numerous cancers with activation or inhibition a topic of debate. To assess whether purinergic signalling could be a viable target in primary bone cancer a systematic review for relevant primary literature published in PubMed, MEDLINE and Web of Science was performed. Search terms were formulated around three separate distinct topics; expression of P2 receptors in primary bone cancer models, P2 receptor signalling pathways involved and the functional consequences of P2 receptor signalling. Searching identified 30 primary articles after screening and eligibility assessments. This review highlights the diverse expression, signalling pathways and functional roles associated with different P2 receptors in primary bone cancers and provides a systematic summary of which P2 receptors are exciting targets to treat primary bone cancer and its associated symptoms.