The neurochemical and behavioral deficits associated with a loss of reelin in animal models of depression, together with the rescuing of behavioral phenotypes by addition or overexpression of reelin in models of several neuropsychiatric disorders, strongly suggest that tackling the reelin system (i.e., by the addition of recombinant reelin, by activating the reelin receptors VLDLR and/or ApoER2, or by neuroprotection of reelin-positive cells) could be a good strategy for the development of novel antidepressants. This evidence concerns the gene RELN and major depressive disorder.