Mitochondrial function depends on the synchronised expression of nuclear and mitochondrial-encoded genes. The expression of many nuclear genes is sensitive to the functional state of mitochondria. Mitochondria containing mutated mtDNA populations have been shown to withstand stress to a high level of tolerance. The prolonged survival of cells that are devoid of mitochondrial DNA is further evidence for the existence of this adaptive response. Yeast cells lacking the mitochondrial genome configure their pattern of nuclear gene expression to accommodate changes in nutrient availability and in response to different stress conditions. Little is known about the signalling pathways that mediate the adaptive response in mammalian cells with mitochondrial dysfunction. To gain a global perspective on adaptive responses in cells with mitochondrial dysfunction, we used Affymetrix microarray technology to compare the whole genome transcription profile of Namalwa cells (rho(+)) to that of a Namalwa cell depleted of mitochondrial DNA (rho degrees ). Our results demonstrate that rho degrees Namalwa induce genes encoding hypoxia target proteins, mitochondrial ribosomal proteins, transport channels, tRNA synthetases and enzymes of the glycolytic pathway and the fatty oxidation pathway suggesting that hypoxia and the ensuing cellular adaptations could play an important adaptive role in cells with mitochondrial dysfunction.