Gastro-oesophageal reflux disease (GORD or GERD) is a very common disorder, and advancement in drug development over the years has markedly improved disease management. Proton pump inhibitors (PPIs) remain the mainstay of treatment for GERD due to their profound and consistent inhibitory effect on acid secretion. However, PPIs do not reduce the number of reflux events and do not provide long-term cure for GERD. In addition, although the safety profile of PPIs is excellent, recent population-based studies have suggested that long-term PPI use may be associated with a variety of adverse events. They include osteoporosis-related hip and spine fractures, community-acquired and nosocomial pneumonia, various enteric and non-enteric infections, fundic gland polyps and many others. Consequently, there is growing interest by patients and physicians alike in current, as well as future, non-PPI-related therapeutic strategies for GERD. This includes repositioning histamine H2 receptor antagonists and prokinetics in our current GERD therapeutic algorithms and a resurgence of non-medical therapeutic modalities for GERD, such as anti-reflux surgery, endoscopic treatment, alternative and complementary medicine and psychological interventions. Furthermore, there will be renewed efforts in further developing new medical and non-medical therapeutic modalities for GERD.