For years the design of κ-opioid receptor (KOR) agonists focussed on generating yet more potent and selective ligands that could access the CNS. As it became apparent that this approach was not going to provide analgesics without significant side effects, effort was directed towards the design of peripherally-acting ligands. This line of research has continued in recent years, together with work towards ligands with a mixed KOR/μ-opioid receptor (MOR) profile. In the area of KOR antagonists, significant advances have been made since the discovery of norbinaltorphimine (norBNI). These studies have provided significant insight into the structural determinants for selective interaction with the KOR. This has led to a number of new classes of KOR antagonist being discovered using rational drug design techniques. This review of the patent literature covering the years 2000 – 2003 will focus on these activities and describe the therapeutic potential of these compounds.