The interaction of the kappa-opioid receptor with arylacetamide and benzomorphan derivatives acting as agonists was modeled through pharmacophore-based and docking calculations. Potentially bioactive conformations of representative ligands (U-50,488 and its benzo-fused analogues 4 and 6 for arylacetamides and MPCB for benzomorphans) were identified by systematic conformational analysis and docked into a 3D model of the kappa-receptor. The obtained complexes, refined by energy-minimization and molecular dynamics, were evaluated for their consistency with structure-activity relationships and site-directed mutagenesis data. The following interactions are hypothesized to govern the ligand-receptor recognition process: (i) a salt bridge between the Asp138 carboxylate and the protonated nitrogen of the bound agonist; (ii) a hydrogen bond donated by the Tyr312 hydroxyl to the carbonyl oxygen of arylacetamides and MPCB; (iii) hydrophobic interactions established by the dichlorophenyl moiety of arylacetamides and the pendant phenyl ring of MPCB with the surrounding side chains of Tyr312, Leu224, Leu295, and Ala298; (iv) a pi-stacking contact between the Tyr312 side chain and the phenyl ring of arylacetamides; (v) a hydrogen bond linking the His291 imidazole ring to the phenolic hydroxy group featured by typical benzomorphans and the arylacetamides 4 and 6.