Since the 50’s, the efficacy drug discovery and development is facing a constant decline. One cause of failure is the inconsistency of observed clinical data with previous basic research and pre-clinical evidence. This dramatically poor translational success of biomedical research is most prominent for example in ischemic stroke, a condition with a high unmet medical need and over a thousand experimental drug targets being unsuccessful. However, eventually this pertains to almost every medical field. Stringent statistical thresholds, reporting negative data and a systematic review / meta-analysis / pRCT approaches and different career and funding incentives may enhance biomedical data validity and overcome risks of bias. To facilitate the deposition and accessibility of negative data systematic reviews and meta-analysis, the pre-clinicaltrials.org database has been founded. Another reason for failure and our current imprecision in medicine are our definitions of diseases, i.e. mostly by organ or symptom, not by mechanism. Systems Medicine will lead to a mechanism-based redefinition of diseases, precision diagnostics and therapies that eliminate both the risk in drug discovery but eventually also the need for further drug discovery. There will be time point in the not so far future where we have all the drugs we need.