Pharmaceutical companies continuously face challenges to deliver new drugs with true medical value. R&D productivity of drug development projects depends on 1) the value of the drug concept and 2) data and in-depth knowledge that are used rationally to evaluate the drug concept’s validity. A model-based data-intensive drug development approach is a key competitive factor used by innovative pharmaceutical companies to reduce information bias and rationally demonstrate the value of drug concepts. Owing to the accumulation of publicly available biomedical information, our understanding of the pathophysiological mechanisms of diseases has developed considerably; it is the basis for identifying the right drug target and creating a drug concept with true medical value. Our understanding of the pathophysiological mechanisms of disease animal models can also be improved; it can thus support rational extrapolation of animal experiment results to clinical settings. The Systems Biology approach, which leverages publicly available transcriptome data, is useful for these purposes. Furthermore, applying Systems Pharmacology enables dynamic simulation of drug responses, from which key research questions to be addressed in the subsequent studies can be adequately informed. Application of Systems Biology/Pharmacology to toxicology research, namely Systems Toxicology, should considerably improve the predictability of drug-induced toxicities in clinical situations that are difficult to predict from conventional preclinical toxicology studies. Systems Biology/Pharmacology/Toxicology models can be continuously improved using iterative learn–confirm processes throughout preclinical and clinical drug discovery and development processes. Successful implementation of data-intensive drug development approaches requires cultivation of an adequate R&D culture to appreciate this approach.