Gastroesophageal reflux disease (GERD) can present with both typical symptoms such as heartburn and regurgitation as well as atypical symptoms. These symptoms may include chest pain, asthma, chronic cough, hoarseness, otitis media, atypical loss of dental enamel, idiopathic pulmonary fibrosis, recurrent pneumonia, chronic bronchitis and even sudden infant death. The diagnosis of GERD in these patients can often present a challenge and usually requires a combination of selected testing and therapeutic trials. Acid suppression by using proton pump inhibitors remains the treatment of choice in GERD, but some patients will also respond well to antireflux surgery. This article addresses the presentations, diagnostic challenges, and therapeutic opportunities in GERD patients with atypical presentations.