A typical feature of human prion diseases (PrDs) is the rapid decline to terminal illness that patients experience after symptom onset, with the most common phenotype, sporadic Creutzfeldt–Jakob disease (sCJD), frequently progressing from full independence to requiring palliative care over the course of weeks. A similar disease course is often observed in the much less common genetic CJD, especially when associated with the more common pathogenic mutations E200K and D178N. Therefore, the temporal therapeutic window is greatly reduced in PrDs compared with other dementias. There are currently no recognised reliable indicators of imminent or prodromal disease preceding the onset of overt, rapid, and currently unalterable decline. The advent of disease-modifying therapies will further underscore the need to expedite the time taken to achieve an accurate diagnosis in order to improve patient outcomes, highlighting the importance of detecting PrDs as early as possible in their clinical evolution. This review discusses what we currently know about pre-symptomatic and prodromal PrD derived from incidental case reports, limited preclinical cohort studies, and large-scale retrospective tissue screening programmes, contextualising the utility of current diagnostic tools and biomarkers for the detection of PrDs at these nascent disease stages.