BACKGROUND AND PURPOSE: Glioblastoma (GBM) is the most aggressive brain tumour in the central nervous system, but the current treatment is very limited and unsatisfactory. PGE -initiated cAMP signalling via EP and EP receptors is involved in the tumourigenesis of multiple cancer types. However, whether or how EP and EP receptors contribute to GBM growth largely remains elusive. EXPERIMENTAL APPROACH: We performed comprehensive data analysis of gene expression in human GBM samples and determined their expression correlations through multiple bioinformatics approaches. A time-resolved fluorescence energy transfer (TR-FRET) assay was utilized to characterize PGE -mediated cAMP signalling via EP and EP receptors in human glioblastoma cells. Using recently reported potent and selective small-molecule antagonists, we determined the effects of inhibition of EP and EP receptors on GBM growth in subcutaneous and intracranial tumour models. KEY RESULTS: The expression of both EP and EP receptors was upregulated and highly correlated with a variety of tumour-promoting cytokines, chemokines, and growth factors in human gliomas. Further, they were heterogeneously expressed in human GBM cells, where they compensated for each other to mediate PGE -initiated cAMP signalling and to promote colony formation, cell invasion and migration. Inhibition of EP and EP receptors revealed that these receptors might mediate GBM growth, angiogenesis, and immune evasion in a compensatory manner. CONCLUSION AND IMPLICATIONS: The compensatory roles of EP and EP receptors in GBM development and growth suggest that concurrently targeting these two PGE receptors might represent a more effective strategy than inhibiting either alone for GBM treatment.