Although the clinical validity of a number of pharmacogenetic markers is nowadays a matter of fact, and led authoritative scientific consortia as the Dutch Pharmacogenetic Working Group (DPWG) and the Clinical Pharmacogenomics Implementation Consortium (CPIC) to publish pharmacogenetic guidelines, the clinical implementation in real life remains challenging. Ubiquitous Pharmacogenomics (U-PGx) program is a coordinated effort that put together scientific and clinical expertise in the pharmacogenomic field, to implement the pre-emptive pharmacogenomic approach in the clinical practice in Europe, and to demonstrate its benefit in both patients’ clinical outcome and quality of life, with an economic advantage for the healthcare system. The project is conceived as a clinical trial that will compare 4,000 patients, pre-emptively genotyped for a panel of pharmacogenes included in the DPWG guidelines, and treated accordingly, with 4,000 controls treated with the standard of care. All the genetic data will be prospectively collected and fully embedded into the patient’s clinical record. An electronic clinical decision support system will be developed to alert physicians and pharmacists when a drug is being prescribed or dispensed to a patient with a risky genotype. U-PGx will test and harmonize this approach in seven healthcare environments (The Netherlands, Spain, UK, Italy, Austria, Greece, Slovenia) to set the basis for a future European healthcare system where an ‘effective treatment optimization will be accessible to every European citizen’ (www.upgx.eu).