Efforts in the design and discovery of selective α7 nicotinic acetylcholine receptor (nAChR) agonists were both facilitated and hampered by observation that ligands can show dual affinity at both the 5-HT3 receptor (5-HT3R) and nAChR. The 5-HT3R and nAChRs are both part of the Cys-loop superfamily of ligand-gated ion channels. Further, there is significant sequence homology between 5-HT3R and α7 nAChR in the ligand recognition domain. Previously reported potent α7 nAChR agonists lacked selectivity versus 5-HT3R, and antagonist activity at 5-HT3R often translated into agonism at α7 nAChR. The crossover in affinity might be explained by pharmacophoric elements common to both 5-HT3R and α7 nAChR: a basic amine (protonated at physiological pH) provides for a cationπ interaction; a hydrogen-bond acceptor, e.g., a carbonyl group, forms a hydrogen bond; and aromatic moieties participate in ππ interactions. In view of reported side effects, i.e., constipation, asymptomatic electrocardiogram changes, and arrhythmias, associated with 5-HT3R antagonists, efforts of research groups were focused on design of ligands specifically interacting with only the α7 nAChR to maximize the therapeutic effect and minimize the adverse effects. Over the past 10 years, drug discovery efforts significantly expanded the quantity and quality of selective α7 nAChR ligands. Those have been summarized in several excellent reviews. Despite early skepticism centered around the rapid desensitization of the α7 nAChR and the hypothesis that agonists might not be functional agonists in vivo, 10 of them have already been advanced to clinical trials. In this review, we highlight the most advanced and characterized (especially in vivo) selective α7 nAChR orthosteric and allosteric α7 nAChR modulators.