Electron microscopy imaging of post-mortem human brain (PMHB) comes with a unique set of challenges due to numerous parameters beyond the researcher's control. Nevertheless, the wealth of information provided by the ultrastructural analysis of PMHB is proving crucial in our understanding of neurodegenerative diseases. This review highlights the importance of such studies and covers challenges, limitations and recent developments in the application of current EM imaging, including cryo-ET and correlative hybrid techniques, on PMHB.