This presentation highlights the major steps and events that have revolutionised whole body M&S from its academic origins in anesthesiology and cardiovascular physiology to its current pervasive place in industrial drug development and regulatory review, and beyond. This did not occur by accident. With initial application in pharmacokinetics (PK), M&S expanded into PK/PD, dose-response and population approaches, again principally initially spearheaded by academia. Impetus from the regulatory agencies, particularly FDA, came to the fore in the early ‘90s and has continued since then with a steady stream of guidances and initiatives, including the specific inclusion of M&S in the recent PDUFA VI and other initiatives, all of which in turn has helped nurture and galvanise industry generally to adopt M&S as an integral science-driven component of drug development, including clinical trial design. Initially descriptive and empirical, M&S is now evolving to become increasingly mechanistic, particularly seen with the adoption of physiologically-based pharmacokinetics (PBPK) and more recently QSP (quantitative systems pharmacology), to help improve the quality of predictions and the efficiency of drug development. In doing so these models have become warehouses of knowledge of drugs helping to address many questions and issues arising pre- and post-registration. These models are dynamic, and so are their applications. Expect further evolution in this fermenting area.