More than 50 years after its initial description, transient global amnesia (TGA) remains one of the most enigmatic syndromes in clinical neurology. Recent MRI data suggest that a transient perturbation of hippocampal function is the functional correlate of TGA because focal diffusion lesions can be selectively detected in the CA1 field of the hippocampal cornu ammonis. Although various factors, such as migraine, focal ischaemia, venous flow abnormalities, and epileptic phenomena, have been suggested to be involved in the pathophysiology of TGA, the factors triggering the emergence of these lesions are still elusive. Recent data suggest that the vulnerability of CA1 neurons to metabolic stress plays a pivotal part in the pathophysiological cascade, leading to an impairment of hippocampal function during TGA. In this Review, we discuss clinical aspects, new imaging findings, and recent clinical–epidemiological data with regard to the phenotype, functional anatomy, and putative cellular mechanisms of TGA.