The most relevant target for the treatment of refractory gastroesophageal reflux disease (GERD) is controlling the occurrence of transient lower esophageal relaxations (TLESR), which represent the main mechanism of all types of reflux. Drugs in development that have this mechanism of action are now described as reflux inhibitors. The most promising among these appear to be mGluR5 agonists and GABAB receptor agonists, which reduce the number of reflux episodes and improve reflux-related symptoms. Reflux inhibitors appear to have a potential role in the management of refractory GERD as add-on therapy in combination with PPI. Future studies will establish the safety and tolerability of the new anti-reflux therapy.