The concept of a “Learning Health System” (LHS) is emerging as a new paradigm in healthcare. We present an overview of LHS functions and concepts, then an analysis of the ways in which Human Factors (HF) can contribute to and benefit from LHS. Successful implementation of an LHS will require the engagement of the HF community, and to this end the HF community will benefit from understanding the LHS. In order to effectively contribute, HF professionals must understand the complexities of the LHS, as well as the leverage points on which HF professionals can act.