Few scientific contributions have made significant impact unless there was a champion who had the vision to see the potential for its use in seemingly disparate areas-and who then drove active implementation. In this paper, we present a historical summary of the development of non-linear mixed effects (NLME) modeling up to the more recent extensions of this statistical methodology. The paper places strong emphasis on the pivotal role played by Lewis B. Sheiner (1940-2004), who used this statistical methodology to elucidate solutions to real problems identified in clinical practice and in medical research and on how he drove implementation of the proposed solutions. A succinct overview of the evolution of the NLME modeling methodology is presented as well as ideas on how its expansion helped to provide guidance for a more scientific view of (model-based) drug development that reduces empiricism in favor of critical quantitative thinking and decision making.