The 7-type nicotinic acetylcholine receptor is one of the most unique and interesting of all the members of the cys-loop superfamily of ligand-gated ion channels. Since it was first identified initially as a binding site for -bungarotoxin in mammalian brain and later as a functional homomeric receptor with relatively high calcium permeability, it has been pursued as a potential therapeutic target for numerous indications, from Alzheimer disease to asthma. In this review, we discuss the history and state of the art for targeting 7 receptors, beginning with subtype-selective agonists and the basic pharmacophore for the selective activation of 7 receptors. A key feature of 7 receptors is their rapid desensitization by standard "orthosteric" agonist, and we discuss insights into the conformational landscape of 7 receptors that has been gained by the development of ligands binding to allosteric sites. Some of these sites are targeted by positive allosteric modulators that have a wide range of effects on the activation profile of the receptors. Other sites are targeted by direct allosteric agonist or antagonists. We include a perspective on the potential importance of 7 receptors for metabotropic as well as ionotropic signaling. We outline the challenges that exist for future development of drugs to target this important receptor and approaches that may be considered to address those challenges. SIGNIFICANCE STATEMENT: The 7-type nicotinic acetylcholine receptor (nAChR) is acknowledged as a potentially important therapeutic target with functional properties associated with both ionotropic and metabotropic signaling. The functional properties of 7 nAChR can be regulated in diverse ways with the variety of orthosteric and allosteric ligands described in this review.