Tobacco control and public health have evolved into a complex set of interconnected and largely self-organizing systems. Their components include international, national, and local governmental agencies; individual advocacy groups; policy makers; health care professionals; nonprofit foundations; and the general population itself. The issues require the exploration of approaches and methodologies that speak to the evolving, dynamic nature of this systems environment. This monograph focuses on the first two years of the Initiative on the Study and Implementation of Systems (ISIS), which was funded by the National Cancer Institute to examine the potential for systems thinking in tobacco control and public health. ISIS explored the general idea of a systems thinking rubric encompassing a great variety of systems-oriented methodologies and approaches. Four approaches have particular promise for their applicability to tobacco control and public health and thus were chosen as areas for initial investigation: (1) organizing and managing as a system, (2) system dynamics and how to model those dynamics, (3) system networks and their analysis, and (4) systems knowledge and its management and translation. As a transdisciplinary effort that linked both tobacco control stakeholders and systems experts, ISIS combined a number of exploratory projects and case studies within these four approaches with a detailed examination of the potential for systems thinking in tobacco control. Its end product was a set of expert consensus guidelines for the future implementation of systems thinking and systems perspectives for tobacco control and public health.