The quest for NR2B subtype selective NMDA antagonists started almost twenty years ago. The structure of ifenprodil, the prototype of this group of compounds, inspired many medicinal chemists in several research units. Different approaches led to the identification of the pharmacophore and several distinct classes of compounds containing this pharmacophore. From these studies a few drug candidates emerged and clinical trials proved the viability of the concept. This article attempted to follow the evolution from ifenprodil, a multiple ligand, to selective NR2B antagonists.