The chapter illustrates the changes that have taken place within the pharmaceutical industry over the past few years. The first compounds were identified from experiments in animal tissue in which the nature of the receptors involved was poorly characterized. Receptor subtypes were subsequently identified, and for some time, species differences caused confusion that was subsequently resolved with the use of recombinant receptors expressed in cell lines and careful pharmacological analysis. The use of human recombinant receptors led to the identification of selective agents that were used to define the receptor subtypes present in native tissue preparations. Thus, in the brain, the terminal 5-hydroxytryptamine (HT) autoreceptor was identified as being of the 5-HT1B subtype. However, the use of highly expressed recombinant receptors in functional assays led to the further complication that antagonists in tissue were shown to be partial agonists in the cell-based functional assays where the recombinant receptor was expressed. Using the latter technology, selective inverse agonists were identified but many of the compounds identified as partial agonists in the recombinant cell lines have been shown to be antagonists in native tissue.