Objectives: Gastroesophageal reflux disease is one of the most common gastrointestinal diagnoses. This disorder causes many symptoms and may induce the development of Barret’s esophagus and esophageal adenocarcinoma. Proton pump inhibitors are the most used treatment and, usually, are prescribed for once-daily dosing before breakfast. However, many patients describe night-time symptoms, a period when an increase of basal gastric acid secretion occurs. Therefore, this evidence-based review was performed in order to understand which is the best regimen for proton pump inhibitor intake. Methods: The MeSH words ‘proton pump inhibitors’, ‘gastro-oesophageal reflux’, GERD, and pH were chosen to search for synopses, guidelines, meta-analysis, systematic reviews, and original papers, published after 2008 in the databases MEDLINE, National Guideline Clearinghouse, NHS Evidence, Canadian Medical Association, TRIP Database, The Cochrane Library, DARE and Bandolier in English, French, Spanish and Portuguese. A search in the Índex de Revistas Médicas Portuguesas with the words “inibidores das bombas de protões”, “refluxo gastroesofágico”, DRGE, and pH was also performed. The search retrieves 2,546 articles, from those, three were used in this review. Results: Three prospective studies that evaluate the effects of dosage and/or timing of proton pump inhibitors intake in gastric pH were obtained. These studies indicate that, in patients with predominant night-time symptoms, intake before dinner achieves better results than before breakfast. Additionally, doubling the dose reduces symptoms and the time of pH lower than four. Conclusion: Symptom timing and patient compliance are crucial when choosing the therapeutic regimen. The timing of proton pumps inhibitors intake should be associated with the symptom’s timing; C-level of recommendation.