The world of tobacco control has become increasingly complex over the past several decades. It involves more extensive collaborations; new structures and configurations for coordinating efforts; and multilevel social, professional, and knowledge networks to improve information sharing for public health. Given such complexity, there has been a corresponding increased need to address tobacco control issues using a systems perspective that enables one to better understand and navigate the dynamic and evolving nature of the terrain to achieve the next generation of improved health outcomes. This monograph describes the results of the initial two years of the Initiative on the Study and Implementation of Systems (ISIS), a four-year project. This initiative is one of the first major coordinated efforts to study and implement a systems thinking perspective using several systems approaches and methodologies that appeared to be promising for tobacco control in itself and as an exemplar for other complex issues in today's public health environment. In the ancient, revered Egyptian myth, the goddess Isis breathed clean air into her late husband Osiris to restore him to life. In analogous fashion, the ISIS project hopes to contemporize the myth in a tobacco control context and encourage systems perspectives that have the potential to help people breathe cleaner air and be restored to a smoke-free life. Although this work is aimed at the efforts of the tobacco control community, the word "tobacco" intentionally appears only in the subtitle of this monograph. That is because ISIS was a research effort that focused on the tobacco control environment to examine how to apply systems approaches to issues that have become endemic throughout public health, including the need for: Better understanding of outcomes, including the unintended consequences of complex interventions and events; Effective capture, dissemination, and management of knowledge throughout the multilayered public health system; More efficient organization and linkage of the efforts of multiple, diverse stakeholders; Adoption of evidence-based practices that inform practice and improve outcomes; Strengthening of collaborative networks of scientists, policy makers, government and foundation managers, practitioners, and the public. This work was undertaken to help address some of the fundamental organizational issues in tobacco control and, by corollary, much of public health. The goal was to investigate the potential of integrated, systems-based approaches to facilitate the efforts of all stakeholders to make substantive changes in public health outcomes.