This Feature Article highlights some of the key challenges within the field of metabolomics and examines what role separation and analytical sciences can play to improve the use of metabolomics in biomarker discovery and personalized medicine. Recent progress in four key areas is highlighted: (i) improving metabolite coverage, (ii) developing accurate methods for unstable metabolites including in vivo global metabolomics methods, (iii) advancing inter-laboratory studies and reference materials and (iv) improving data quality, standardization and quality control of metabolomics studies.