Information systems are increasingly being implemented by organizations that are a part of the public health ecosystem. By incentivizing the adoption and use of health information technology systems generally and in public health in particular, United States federal laws have spurred these practices into commonplace occurrences. As the different fields within the health care sector began using their own versions of these information systems (i.e., homegrown versions or condition specific), the heterogeneous nature and lack of interoperability of these systems needed to be addressed. To effectively coordinate public health improvement initiatives, public health and health care ecosystems must have strong interprofessional collaborations that lead to cohesive actionable insights instead of relying heavily on health informaticists as translators. The health informaticist must additionally contribute to interoperability efforts, work to resolve data harmonization issues, and refine how to extract meaning from available data in diverse health information systems to inform the advancement of human health. Data receivers must be able to access accurate data from information systems and electronic health records to make interpretations for actionable interprofessional objectives to improve public health outcomes. Semantic interoperability advancements can propagate more efficient learning and knowledge of health systems with shared goals among health care stakeholders. This chapter looks into the opportunities and challenges impacting the use of public health information systems by health informaticists and health care stakeholders across diverse health care ecosystems.