Memories are our reservoir of knowledge and thus, are crucial for guiding decisions and defining our self. The physical correlate of a memory in the brain is termed an engram and since decades helps researchers to elucidate the intricate nature of our imprinted experiences and knowledge. Given the importance that memories have for our lives, their impairment can present a tremendous burden. In this review we aim to discuss engram malfunctioning across diseases, covering dementia-associated pathologies, epilepsy, chronic pain and psychiatric disorders. Current neuroscientific tools allow to witness the emergence and fate of engram cells and enable their manipulation. We further suggest that specific mechanisms of mnemonic malfunction can be derived from engram cell readouts. While depicting the way diseases act on the mnemonic component – specifically, on the cellular engram – we emphasize a differentiation between forms of amnesia and hypermnesia. Finally, we highlight commonalities and distinctions of engram impairments on the cellular level across diseases independent of their pathogenic origins and discuss prospective therapeutic measures.