The NIH Pragmatic Trials Collaboratory supports the design and conduct of 32 embedded pragmatic clinical trials, and many of these trials rely on data from the electronic health record (EHR) to monitor outcomes and/or use functionality provided by the EHR platform to deliver the intervention. Given the complexity and dynamic nature of EHR systems, study teams have encountered challenges in use of the EHR for these purposes, including challenges related to local implementation of trial interventions, rapid technology evolution, EHR updates, and transitions in EHR systems. In this article, we share case examples and lessons learned, and suggest that teams need to be aware of-and perhaps proactively investigate- possible changes to EHR systems and data that will affect the delivery of interventions and the integrity and safety of pragmatic clinical trials.