A therapeutic drug ideally targets the underlying molecular disease mechanisms. Hence providing evidence to redefine ‘disease’, namely no longer by a symptom or affected organ (phenotype), but by the molecular mechanism that causes it, has a crucial importance for drug discovery. However, current strategy in bio-medical research and drug discovery are in a reproducibility and translation crisis. Most drugs relief only symptoms or normalise risk factors but do not target the causal mechanism of disease and for most diseases these mechanisms are not known. To eliminate these problems, and to reveal druggable mechanisms we aim to expand the hypothesis of a network of all human diseases (the diseasome) to completeness, re-engineer and validate it to a network of all active drugs (the drugome) and exploit this approach for drug discovery to repurpose approved drugs that target a mechanism shared by a cluster of disease phenotypes. We have an interdisciplinary team dedicated to a three-fold ”in silico–experimental–clinical” approach to change the definition of disease to mechanism-based. Our approach and drugome will yield mechanism-based therapeutics allowing, in a selected subset of cases, for immediate clinical drug repurposing. Based on a network of disease-disease relationships and clusters, we have recently repurposed the primarily cardio-pulmonary target, soluble guanylate cyclase (sGC), as a promising therapeutic target for brain ischemia (http://bmcpharmacoltoxicol.biomedcentral.com/articles/10.1186/2050-6511-16-S1-A39).