Persistence of cancer stem cells has been associated with disease relapse and drug resistance in a variety of malignancies, including acute myeloid leukaemia (AML) and breast, colon, and prostate cancers. One of the fundamental properties of cancer stem cells is their intrinsic capacity to self-renew. Previous studies have established beta-catenin as the central driver of self-renewal in cancer stem cells. More recent studies have shown that beta-catenin is required for the establishment of leukemic stem cells (LSC) in mixed lineage leukaemia (MLL)-AML. However, targeted inhibition of beta-catenin signalling has been hampered by the lack of pathway components amenable to pharmacological inhibition. Here we have identified a novel beta-catenin regulator, GPR84, a member of the G protein-coupled receptor family that represents a highly tractable class of drug targets. Our studies have shown that GPR84 simultaneously augments both β-catenin signalling and an oncogenic transcription program essential for the establishment of leukemia; and that aberrant activation of GPR84 is required for the maintenance of LSC in vivo. Microarray analysis of gene expression and subsequent quantitative real-time PCR also identified the proto-oncogene Bcl11a to be a new downstream target of GPR84. Significantly, treatment with simvastatin, a potent Bcl11a inhibitor, impaired LSC growth and survival, while GPR84 overexpression partially rescued this deficient phenotype in vitro (P=0.0094). Hence our results suggest that GPR84/β-catenin signalling is likely to represent an attractive therapeutic target in AML and simvastatin may be a promising candidate agent to eliminate AML LSC.