The past decade of population research for diabetes has seen a dramatic proliferation of the use of real-world data (RWD) and real-world evidence (RWE) generation from non-research settings, including both health and non-health sources, to influence decisions related to optimal diabetes care. A common attribute of these new data is that they were not collected for research purposes yet have the potential to enrich the information around the characteristics of individuals, risk factors, interventions, and health effects. This has expanded the role of subdisciplines like comparative effectiveness research and precision medicine, new quasi-experimental study designs, new research platforms like distributed data networks, and new analytic approaches for clinical prediction of prognosis or treatment response. The result of these developments is a greater potential to progress diabetes treatment and prevention through the increasing range of populations, interventions, outcomes, and settings that can be efficiently examined. However, this proliferation also carries an increased threat of bias and misleading findings. The level of evidence that may be derived from RWD is ultimately a function of the data quality and the rigorous application of study design and analysis. This report reviews the current landscape and applications of RWD in clinical effectiveness and population health research for diabetes and summarizes opportunities and best practices in the conduct, reporting, and dissemination of RWD to optimize its value and limit its drawbacks.