SummaryIn recent years, we have witnessed substantial progress in the use of clinical informatics systems to support clinicians during episodes of care, manage specialised domain knowledge, perform complex clinical data analysis and improve the management of health organisations’ resources. However, the vision of fully integrated health information eco systems, which provide relevant information and useful knowledge at the point-of-care, remains elusive. This journal Focus Theme reviews some of the enduring challenges of interoperability and complexity in clinical informatics systems. Furthermore, a range of approaches are proposed in order to address, harness and resolve some of the many remaining issues towards a greater integration of health information systems and extraction of useful or new knowledge from heterogeneous electronic data repositories.