This Special Issue of the European Journal for Biomedical Informatics is dedicated to the International HL7 Interoperability Conference 2018 “Mastering the Interoperability Challenge” (IHIC 2018), 11-12 July 2018 in Portsmouth, UK (http://ihic.info/2018). It contains papers selected by an independent peer review process, strictly performed by experts from countries different from the authors’ country of residence.