Healthcare system is fast evolving with the digitization of health information. Electronic health record (EHR) is generated from various sources like hospitals, laboratories, mobile devices, IoT, and social media. EHR data collected for a person cumulatively give information about patient’s health history. There need to be schemes to transfer EHR data among different healthcare providers in a secure and efficient manner to provide better quality healthcare experience. Interoperability allows transferring information among various stakeholders in the medical domain. Syntactic interoperability allows transferring data among different systems, whereas semantic interoperability enables different systems to interpret meaningfully and accurately exchange data. This chapter builds the case for semantic interoperable EHR systems that enable the healthcare systems to work together and achieve better patient outcomes and effective healthcare. Semantic interoperable systems with artificial intelligence, big data analytics, and data mining help in making real-time decisions for better care. It also reviews the current work, benefits, and challenges in the area of semantically interoperable EHR systems and highlights research direction for the same.