Altered cellular metabolism has emerged as a potentially important aspect in understanding tumour biology and may represent a novel therapeutic target. We have used an integrated approach to study metabolic reprogramming in pancreatic cancer - combining genomics, metabolomics, and phenotypic analysis on a unique cohort of patient-derived pancreatic cancer cell lines (PDCLs). Pancreatic cancer has a devastating prognosis, with five-year survival less than 5% and severely restricted treatment options. Although accumulation of mitochondrial mutations has been observed in various tumour types, including pancreatic cancer, to date there has been little effort to directly link these to metabolic phenotype.We identified somatic mutations in the mitochondrial genomes (mtDNA) of pancreatic tumours. Mutations were also identified in a targeted study of ~1000 nuclear genes important for mitochondrial function and metabolism. Phenotypic analysis of pancreatic PDCLs showed metabolic changes consistent with mitochondrial dysfunction. Metabolomic and radiolabelled substrate utilisation assays indicate induction of reductive glutamine metabolism and increased anabolic biosynthesis in pancreatic tumour cells.Hence, the heterogeneous genomic landscape of pancreatic tumours may converge on common metabolic phenotypes, with individual tumours adapting to increased anabolic demands via different genetic mechanisms. This model predicts a novel therapeutic strategy for pancreatic cancer through targeting key enzymes in reductive glutamine metabolism and fatty acid biosynthesis. More recently, we have been applying similar approaches to understanding the role of fatty acid metabolism in breast cancer.