Whereas short-term memory lasts from minutes to hours, long-term memory (LTM) can last for days or even an entire lifetime. LTM generally forms after spaced repeated training sessions and involves the regulation of gene expression, thereby implicating transcription factors in the initial steps of LTM establishment. However, the direct participation of effector genes in memory formation has been rarely documented, and many of the mechanisms involved in LTM formation remain to be understood. Here we describe a Drosophila melanogaster mutant, crammer (cer), which shows a specific LTM defect. The cer gene encodes an inhibitor of a subfamily of cysteine proteinases, named cathepsins, some of which might be involved in human Alzheimer's disease. The Cer peptide was found in the mushroom bodies (MBs), the Drosophila olfactory memory centre and in glial cells around the MBs. The overexpression of cer in glial cells but not in MB neurons induces a decrease in LTM, suggesting that Cer might have a role in glia and that the concentration of the Cer peptide is critical for LTM. In wild-type flies, cer expression transiently decreases after LTM conditioning, indicating that cysteine proteinases are activated early in LTM formation.