Metabolomics provides a direct functional read-out of the physiological status of an organism and is in principle ideally suited to describe someone's health status. Whereas only a limited number of small metabolites are used in the clinics, in inborn errors of metabolism an extensive repertoire of metabolites are used as biomarkers. We discuss that the proper clinical phenotyping is crucial to find biomarkers and obtain biological insights for multifactorial diseases. This requires to study the phenotype dynamics including the concepts of homeostasis and allostasis, that is, the ability to adapt and cope with a challenge. We also elaborate that biology-driven metabolomics platforms (i.e. development of metabolomics technology driven by the need of studying and answering important biomedical questions) addressing clinically relevant pathways and at the same time providing absolute concentrations are key to allow discovery and validation of biomarkers across studies and labs. Following individuals over years will require high throughput metabolomics approaches, which are emerging for nuclear magnetic resonance spectroscopy and direct-infusion mass spectrometry, but should also include the biochemical networks needed for personalized health monitoring.