This review sought to systematically review the available literature on health information exchange (HIE), the electronic sharing of clinical information across the boundaries of health care organizations. HIE has been promoted as an important application of technology in medicine that can improve the efficiency, cost-effectiveness, quality, and safety of health care delivery. However, HIE also requires considerable investment by sponsors, which have included governments as well as health care organizations. This review aims to synthesize the currently available research addressing HIE effectiveness, use, usability, barriers and facilitators to actual use, implementation, and sustainability, and to present this information as a foundation on which future implementation, expansion, and research can be based. A research librarian designed and conducted searches of electronic databases, including MEDLINE® (1990 to February 2015), PsycINFO® (1990 to February 2015), CINAHL® (1990 through February 2015), the Cochrane Central Register of Controlled Trials (through January 2015), the Cochrane Database of Systematic Reviews (through January 2015), the Database of Abstracts of Reviews of Effects (through the first quarter of 2015), and the National Health Sciences Economic Evaluation Database (through the first quarter of 2015). The searches were supplemented by reviewing reference lists and the table of contents of journals not indexed in the databases we searched. Two investigators reviewed abstracts and the selected full-text articles for inclusion based on predefined criteria. Discrepancies were resolved through discussion and consensus, with a third investigator making the final decision as needed. Data were abstracted from each included article by one person and verified by another. All analyses were qualitative, and they were customized according to the topic. We included 136 studies overall, with 34 on effectiveness, 26 of which reported intermediate clinical, economic, or patient outcomes, and 8 that reported on clinical perceptions of HIE. We also found 58 studies on the use of HIE, 22 on usability and other facilitators and barriers to actual use of HIE, 45 on facilitators or barriers to HIE implementation, and 17 on factors related to sustainability of HIE. The scope of studies identified was limited compared with the actual uses and capabilities of HIE. The outcomes measured and methods of measurement and analysis, for example, were limited and narrowly defined; the issue of potential confounders was not addressed in most studies of effectiveness, and harms were not adequately studied. There was a high degree of heterogeneity in study designs, outcomes, HIE types, and settings across the studies, limiting the ability to synthesize the evidence; no quantitative analyses were possible. The applicability of this evidence base is uncertain because the HIE systems studied were so diverse, and many in existence have not contributed to research in this field. The full impact of HIE on clinical outcomes and potential harms is inadequately studied, although evidence provides some support for benefit in reducing use of some specific resources and achieving improvements in quality-of-care measures. Use of HIE has risen over time, and is highest in hospitals and lowest in long-term care settings. However, use of HIE within organizations that offer it is still low. Barriers to HIE use include lack of critical mass participating in the exchange, inefficient workflow, and poorly designed interface and update features. Studies have identified numerous facilitators and barriers to implementation and sustainability, but the studies have not ranked or compared their impact. To advance our understanding of HIE, future studies need to address comprehensive questions, use more rigorous designs, use a standard for describing types of HIE, and be part of a coordinated systematic approach to studying HIE.