The electronic health record (EHR) represents a rich source of patient information, increasingly being leveraged for cardiovascular research. Although its primary use remains the seamless delivery of health care, the various longitudinally aggregated structured and unstructured data elements for each patient within the EHR can define the computational phenotypes of disease and care signatures and their association with outcomes. Although structured data elements, such as demographic characteristics, laboratory measurements, problem lists, and medications, are easily extracted, unstructured data are underused. The latter include free text in clinical narratives, documentation of procedures, and reports of imaging and pathology. Rapid scaling up of data storage and rapid innovation in natural language processing and computer vision can power insights from unstructured data streams. However, despite an array of opportunities for research using the EHR, specific expertise is necessary to adequately address confidentiality, accuracy, completeness, and heterogeneity challenges in EHR-based research. These often require methodological innovation and best practices to design and conduct successful research studies. Our review discusses these challenges and their proposed solutions. In addition, we highlight the ongoing innovations in federated learning in the EHR through a greater focus on common data models and discuss ongoing work that defines such an approach to large-scale, multicenter, federated studies. Such parallel improvements in technology and research methods enable innovative care and optimization of patient outcomes.