Epidemiological studies on the intergenerational transmission of hyperglycemia and obesity via in utero exposure have established the scientific foundation for the vicious cycle of diabetes and obesity. The findings compel us to address an urgent public health question: how do we break this vicious cycle and implement upstream prevention strategies that are feasible for patients and health care delivery systems? To address this question, it is necessary to work across a continuum of translational research from basic science, epidemiology, and efficacy trials to pragmatic trials, which, along with evaluations of health programs, may lead to implementation of positive changes in clinical care. Three strategies for translating research on diabetes and obesity in pregnancy into prevention are discussed: 1) identifying diagnostic criteria of gestational diabetes mellitus (GDM) practicable in clinical settings to implement treatment and prevention, 2) examining trends in the prevalence of diabetes in pregnancy and related complications across racial/ethnic groups to plan prevention efforts, and 3) developing and evaluating scalable upstream diabetes and obesity prevention interventions. Upstream preventive interventions aimed at breaking the vicious cycle are discussed. Areas of future research needed to break the vicious cycle are identified. Evaluating the effectiveness of programs for the management of pregnancy hyperglycemia is necessary to reduce complications. Understanding racial/ethnic differences in the pathophysiology of GDM and its complications will be important for risk stratification. Pragmatic trials in real-world clinical settings for upstream prevention are needed to break the vicious cycle at the population level. Finally, leveraging basic science with intergenerational studies will inform targeted interventions.