Histone H2A variant, H2A.Z, plays an essential role in transcriptional activation of ERα-dependent genes, cell proliferation, development, and differentiation. High expression of H2A.Z is ubiquitously detected in the progression of breast cancer, and is significantly associated with lymph node metastasis and patient survival. This makes H2A.Z an excellent target for diagnostic and therapeutic interventions. A recent study provides a new insight into the role of H2A.Z within the context of cancer-related genes and further corroborates the emerging link between dysfunction of this histone variant and cancer. Interestingly, the depletion of H2A.Z also causes defective in the stability and integrity of the human genome. These abnormalities include defective chromosome segregation, activation of LINE-1 retrotransposable elements, and changes in cell cycle-related genes. This article also presents the molecular pathways linking H2A.Z to breast cancer and mechanisms have been proposed to explain how altered H2A.Z leads to tumorigenesis. Two strategies are proposed here for anti-tumor treatments of H2A.Z-defective breast cancer. One is to restore H2A.Z function by targeting c-Myc transcription factor and the other is to find potential drug treatment by blocking the activity of H2A.Z-remodelling complex, p400/Tip60.