Studies of TRH and GnRH receptors have revealed much information about the roles of G-proteins and beta-arrestins, as well as receptor residues important for signaling, desensitization and internalization. However, the proteins involved are only just beginning to be identified and characterized. Additional complexity now exists with the observation that these receptors form oligomers in live cells. Indeed, hetero-oligomerization of TRH receptor subtypes 1 and 2 potentially alters interactions with intracellular regulatory proteins. Knowledge of proteins that interact with TRH or GnRH receptors will increase our understanding of receptor function and provide potential drug targets for a range of receptor-associated conditions.