Precision medicin requires the knowledge of constitutive factors of idiosyncratic resilience/vulnerability of a subject to a disease as a prerequisite for a tailored treatment. Phenylketonuria (PKU), a prototypical model of a treatable genetic disorder, has taught us how variable may be the clinical phenotype caused by a monogenic lesion. We are now aware that the biomarkers adopted so far for diagnosis and monitoring of early treated PKU patients are weakly predictive of the outcome in adulthood, leaving unexplained a wide clinical interindividual variability. With new effective (and expensive) treatments on the horizon this gap needs to be bridged. (By Prof. Vincenzo Leuzzi, https://jmg.bmj.com/content/early/2019/09/03/jmedgenet-2019-106278)