Real-world evidence (RWE) studies – which are increasingly required to demonstrate product value in settings that reflect actual care settings – demand different approaches from traditional, randomized clinical trials. Data typically covers outcomes, and may come from observational studies, pragmatic trials, or database studies. This paper discusses best practices to address the most common challenges that arise in engaging and selecting sites for RWE studies, based on Quintiles’ experience with more than 96,000 sites in observational and quality improvement programs in over 100 countries since 2011. These best practices include developing a clear research question and trial strategy, and a protocol that will deliver valid findings by minimizing bias. Innovative and data-driven approaches to feasibility and site engagement can then optimize selection and engagement of appropriate sites and participants, all within target timelines. All critical elements of the site recruitment plan must be in place before site outreach begins, forming a solid foundation for site relationships and the achievement of study timelines. A “back to basics first” approach is outlined to address issues early on and prevent impacts from cascading through later periods of the study. This upfront investment of resources and tactics can improve outcomes and reduce timelines.