Chronic consumption of proton pump inhibitors (PPIs) by patients with gastroesophageal reflux disease is very common, primarily because of their potent and profound effect on acid secretion that results in an unsurpassed rate of symptom resolution and esophageal healing. However, there have been a growing number of reports over the past few years about various side effects caused by chronic PPI treatment. Concerns have been raised by patients and physicians alike about the common practice of prescribing PPIs, often more than once daily, on a long-term basis. As a result, there has been a resurgence of interest in alternative therapeutic modalities for chronic PPI treatment. These include novel endoscopic and surgical techniques, as well as other available therapeutic strategies that are likely to be revisited, such as histamine-2-receptor antagonists, intermittent and on-demand PPI treatment, and antireflux surgery, among others.