We are witnessing a dramatic transformation in the way we do science. In recent years, significant flaws with existing scientific methods have come to light, including lack of transparency, insufficient involvement of stakeholders, disconnection from the public, and limited reproducibility of research findings. These concerns have sparked a global movement to revolutionize scientific practice and the emergence of Open Science. This new approach to science extends principles of openness to the entire research cycle, from hypothesis generation to data collection, analysis, replication, and translation from research to practice. Open Science seeks to remove all barriers to conducting high quality, rigorous, and impactful scientific research by ensuring that the data, methods, and opportunities for collaboration are open to all. Emerging digital technologies and "big data" (see "Ten simple rules for responsible big data research") have further accelerated the Open Science movement by affording new approaches to data sharing, connecting researcher networks, and facilitating the dissemination of research findings. Open scientific practices are also having a profound impact on the health sciences and medical research, and specifically how we conduct clinical research with human participants. Human health research necessitates careful considerations for practicing science in an ethical manner. There is also a particular urgency to human health research since the goal is to help people, so doing good science takes on a different meaning than simply doing science well. It also implores the scientist to reassess the conventional view of human health research as a pursuit conducted by scientists on human subjects, and lays a greater emphasis on inclusive and ethical practices to ensure that the research takes into account the interests of those who would be most impacted by the research. Openness in the context of human health research also raises greater concerns about privacy and security and presents more opportunities for people, including participants of research studies, to contribute in every capacity. At the core of open health research, scientific discoveries are not only the product of collaboration across disciplines, but must also be owned by the community that is inclusive of researchers, health workers, and patients and their families. To guide successful open health research practices, it is essential to carefully consider and delineate its guiding principles. This editorial is aimed at individuals participating in health science in any capacity, including but not limited to people living with medical conditions, health professionals, study participants, and researchers spanning all types of disciplines. We present ten simple rules that, while not comprehensive, offer guidance for conducting health research with human participants in an open, ethical, and rigorous manner. These rules can be difficult, resource-intensive, and can conflict with one another. They are aspirational and are intended to accelerate and improve the quality of human health research. Work that fails to follow these rules is not necessarily an indication of poor quality research, especially if the reasons for breaking the rules are considered and articulated (see rule 6: document everything). While most of the responsibility of following these rules falls on researchers, anyone involved in human health research in any capacity can apply them.