Pharmacophore hypotheses were generated for a series of isoxazolylpiperazine inhibitors selectively acting on the dopamine D4 receptor. HypoGen and HipHop programs in the CATALYST software were used to get insight into the structural features required for the inhibition activity. The HypoGen-generated pharmacophore model, with four features, which include HBAl, HBAl, HpAr, RA, showed high correlation (r = 0.950) and predictive power. It also rationalized the relationships between structure and biological activity of these inhibitors of dopamine D4 receptor. This successful prediction was further validated on several structurally diverse compounds active against dopamine D4 receptor using HipHop method.