Significant gains have been made in the appreciation of pediatrics as an important population in which rationale pharmacotherapy guidance is warranted but often currently lacking. Although the regulatory framework for major improvements in pediatric drug development was implemented in Europe a decade later than the United States, recent efforts, including the 2007 "Better Medicines for Children" initiative, indicate that the awareness of this problem is indeed a global phenomenon. Nevertheless, there still remains a gap between the awareness and the implementation of rationale and scientifically based drug development and applied pharmacotherapy in children. Specifically, a vision of how best to move from empiricism toward a plan that incorporates biologic knowledge about the maturation of physiologic processes as well as the drug- and disease-specific knowledge generated from drug development and applied pharmacotherapy in adults must evolve from the present intentions. Modeling and simulation approaches can facilitate such a vision that ultimately should provide benefit to pediatric patients. Although recent examples of pediatric in silico approaches are compelling, their ultimate value may be in the identification of data and studies that better guide drug therapy and in the education of pediatric caregivers to the principles of clinical pharmacology that underlie optimal pharmacotherapeutic decisions in children.