The term hormesis refers to a biphasic dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition represented by a J-shaped or U-shaped curve, depending on the parameter measured (Calabrese and Baldwin, Hum Exp Toxicol, 2002). Indeed, several, if not all, physiological molecules (i.e. glutamate, glucocorticoids, nitric oxide) are likely to present a hormetic effect, exhibiting opposite effects at high or low concentrations. Here, we focused on amyloid-beta (Ab), a peptide widely known because it is produced in high amounts during Alzheimer's disease (AD). Ab is considered a toxic fragment causing synaptic dysfunction and memory impairment (Selkoe, Science, 2002). However, the peptide is normally produced in the healthy brain and growing evidences indicate that it might have a physiologic function. We have recently demonstrated that picomolar concentrations of Ab42 enhance synaptic plasticity and memory (Puzzo et al, J Neurosci, 2008) and that endogenous Ab is necessary for synaptic plasticity and memory (Puzzo et al, Ann Neurol, 2011). Here, we show that Ab has a hormetic effect on hippocampal synaptic plasticity and memory, tested with Fear Conditioning and Morris water-maze test on wild type mice. Our results suggest that, paradoxically, Ab itself might serve to enhance memory at appropriate concentrations and conditions. These findings raise several issues when designing effective and safe approaches to AD therapy.