High-resolution episcopic microscopy (HREM) is an imaging technique that permits the simple and rapid generation of three-dimensional (3D) digital volume data of histologically embedded and physically sectioned specimens. The data can be immediately used for high-detail 3D analysis of a broad variety of organic materials with all modern methods of 3D visualisation and display. Since its first description in 2006, HREM has been adopted as a method for exploring organic specimens in many fields of science, and it has recruited a slowly but steadily growing user community. This review aims to briefly introduce the basic principles of HREM data generation and to provide an overview of scientific publications that have been published in the last 13 years involving HREM imaging. The studies to which we refer describe technical details and specimen-specific protocols, and provide examples of the successful use of HREM in biological, biomedical and medical research. Finally, the limitations, potentials and anticipated further improvements are briefly outlined.