Medicine and its major intervention, drug therapy, are in an efficacy crisis causing healthcare costs to explode. Current drugs are highly ineffective providing benefit for only every fifth to less patient; the success rate of discovering new drugs is since the 1950’s in a constant decline and by the end of the 2020’s big pharma is predicted to be no longer sustainable. And why should be eternally develop new drugs when we may have already most if the drugs that we need. Repurposing existing drugs in a precise manner, i.e. only for the disease phenotype and patient where it works. One key reason for these failures and shortcomings is our current approach to diseases, i.e. not understanding their underlying causes but rather treating symptoms and too late. Medicine is captured in highly specialised and sub-specialised organ-based silo disciplines. Instead diseases are most likely multi-organ based. Systems Medicine overcomes these obstacles by introducing mechanism-based disease definitions integrating (epi)genetic and (microbi)omic data. This will lead to precise, mechanism-based diagnostics and mechanism-based therapies. Since molecular disease definitions are dysregulated pathways and most pathways are present in several cells and organs, most diseases will be multi-organ, thus abolishing the entire current organ-based structure of medicine and its disciplines.