Steroids, synthesized in peripheral glands or centrally in the brain - the latter being named neurosteroids - exert an important role as modulators of the neuronal activity by interacting with different receptors or ion channels. In addition to the modulation of GABA A , NMDA or cholinergic receptors, neuroactive steroids interact with an atypical intracellular receptor, the σ 1 protein. This receptor has been cloned in several species, and highly selective synthetic ligands are available. At the cellular level, σ 1 agonists modulate intracellular calcium mobilization and extracellular calcium influx, NMDA-mediated responses, acetylcholine release, and alter monoaminergic systems. At the behavioral level, the σ 1 receptor is involved in learning and memory processes, the response to stress, depression, neuroprotection and pharmacodependence. Pregnenolone, dehydroepiandrosterone, and their sulfate esters behave as σ 1 agonists, while progesterone is a potent antagonist. This review will detail the physiopathological consequences of these interactions, focusing on recent results on memory and depression. The therapeutical interest of selective σ 1 receptor agonists in alleviating aging-related cognitive deficits will be discussed.