Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, discovery of probes/drugs for 7TMRs is an important goal of biomedical research. We have begun our research using high throughput screening (HTS) for small molecule ligands (SMLs) for 7TMRs with the receptor for thyroid-stimulating hormone (TSH-R). During this year, we employed a cell-based assay that we developed for activation of TSH-R by SML agonists and a complementary assay for SML inhibitors of TSH stimulation of TSH-R for HTS. We identified new antagonists and agonists for TSH-R that show excellent selectivity because they do not activate or inhibit, respectively, the closely related receptors for luteinizing hormone or follicle-stimulating hormone. These are the first SML agonists and antagonists for TSH-R reported. We continue to modify these compounds chemically to improve their selectivities, affinities and efficacies. Of particular note, is our observation that the antagonist not only inhibits stimulation of TSH-R by TSH but also by thyroid-stimulating antibodies (TsAbs) from patients with Gravess hyperthyroidism. We also identified new, more effective small molecule agonists for TSH-R. These are the first SMLs for TSH-R that have been shown to activate TSH-Rs in normal human thyroid cells and in intact mice. Based on our research, we were asked to write a review on small molecule ligands for the TSH-R.