Summary Profound global challenges to individual and population health, alongside the opportunities to benefit from digital technology, have spawned the concept of the Learning Health System. Learning Health Systems (LHSs)--which can function at organizational, network, regional, and national levels of scale--have the capability of continuous data-driven self-study that promotes change and improvement. The LHS concept, which originated in the U.S. in 2007, is rapidly gaining attention around the world. LHSs require, but also transcend, the secondary use of health data. This paper describes the key features of LHSs, argues that effective and sustainable LHSs must be supported by infrastructures that allow them to function with economies of scale and scope, and describes the services that such infrastructures must provide. While it is relatively straightforward to describe LHSs, achieving them at the high level of capability necessary to promote significant health benefits will require advancements in science and engineering, engaging the field of informatics among a wider range of disciplines. It also follows from this vision that LHSs cannot be built from an imposed blueprint; LHSs will more likely evolve from efforts at smaller scales that compose into larger systems.