Due to their diversity, G-protein-coupled receptors (GPCRs) are major regulators of intercellular interactions. They exert their actions by being activated by a vast array of natural ligands, referred to in this article as "transmitters". Yet each GPCR is highly selective in its ligand recognition. Traditionally, the transmitters were found first and served to characterize the receptors pharmacologically. Since the end of the 1980s, however, it is the GPCRs that are first to be found because they are identified molecularly by homology screening approaches. But the GPCRs found this way suffer of one drawback, they lack their natural transmitters, they are "orphan" GPCRs. Searching for transmitters of orphan GPCRs has given birth to the reverse pharmacology approach that uses orphan GPCRs as targets to identify their transmitters. The most salient successes of the reverse pharmacology approach were the discoveries of 9 novel neuropeptide families. These have enriched our understanding of several important behavioral responses. But the application of reverse pharmacology has also led to some surprising results that question some basic pharmacological concepts. This review aims at describing the history of the orphan GPCRs and their impact on our understanding of biology.