Obesity is a major contributor to many serious health conditions that increase morbidity and reduce quality of life. For example, obesity is a significant risk factor for diabetes, cardiovascular disease, and certain forms of cancer. The prevalence of obesity in children and adults in the USA has dramatically increased in the past four decades [1, 2]. Although some cities and states are showing reductions in rates of childhood obesity, the prevalence is still far above 1970 levels [3–5]. Diabetes currently affects an estimated 25.8 million people in the USA and another 79 million Americans are estimated to be at greatly increased risk of developing diabetes in the next several years [6]. Further, most adults with diabetes in the USA are not meeting the recommended goals for diabetes care [7]. Overweight, obesity, and/or excessive weight gain during pregnancy are also contributing to rising rates of gestational diabetes mellitus which in turn increases risk of future type 2 diabetes in the mother and child. In addition to the considerable impairments to health and quality of life with these conditions, there are also serious economic consequences. The estimated current annual cost of diabetes alone in the USA is $245 billion dollars per year with $176 billion in direct medical costs and the remainder related to reduced productivity [8]. The increasing challenges of obesity and its related health conditions in our society also coincide with a dynamic time for health care in the USA, including changing consumer demands (employers and individuals) and the pressing need to deliver evidence-based care, improve health outcomes for all Americans, and control costs. In communities and in health-care settings, many of the policy and programmatic changes are evidence-informed, but often little is known about population-level effects. Rigorous scientific evaluation of these “natural experiments” can help to more rapidly build an evidence base to inform key stakeholders and policy makers. Evaluation research generally, and rigorous evaluation of natural experiments specifically, is increasingly recognized as an important and appropriate approach to health-related research, particularly in the context of policy and environmental [9, 10] change. The term experiment in natural experiments is something of a misnomer as the implementation of these public health and health-care system policies and programs are not often designed as true experiments. Generally, the term natural experiment refers to an exposure or change that is not directly manipulated by the researcher, but rather the result of policy or program interventions that are varied in their implementation along a number of possible dimensions, such as time, geography, or content. Research that evaluates the real-world implementation of polices and program has some challenges such as the potential for bias, confounding, and threats to casual inference. Despite these limitations, the data from natural experiment research offers unique opportunities to enrich the evidence base and can offer advantages not provided by other research designs, such as improved external validity. This research can provide important data about the impact of a policy or program in real-world settings and populations; see for example the well-known study on the impact of education on health outcomes by Lleras-Muney [11]. Often, these are data that would be very difficult, potentially unethical, and often cost prohibitive to collect in the context of an investigator-initiated randomized experiment [12]. Natural experiment research also allows for the assessment of potential unintended consequences or subgroup differences in response to the program or policy and measurement of implementation fidelity, variability, and process. Since 2010, several institutes and centers (ICs) at the National Institutes of Health have jointly issued funding opportunity announcements intended to support rigorous evaluation of natural experiments related to obesity and/or diabetes outcomes, including the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Cancer Institute (NCI); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Heart, Lung, and Blood Institute (NHLBI); National Institute on Aging (NIA); and the Office of Behavioral and Social Sciences Research (OBSSR). In these funding opportunity announcements, policies are broadly defined to include public policies at local, state, and federal levels of government and organizational level policies, such as those implemented by large organizations, worksites, or school districts. Polices can be formal such as laws and regulations or informal such as guidelines and procedures. Program is defined as a set of activities initiated by governmental or other organizational bodies to enhance obesity prevention and control.