Proton pump inhibitors (PPIs) are widely used in the United States due to their recognized efficacy and safety profile. They are often prescribed to patients with rheumatic diseases including systemic sclerosis (SSc) and rheumatoid arthritis (RA) for reduction and prevention of gastrointestinal (GI) manifestations including gastroesophageal reflux disease (GERD) and upper GI bleeds. Emerging studies have recognized risks associated with PPI therapy but are supported by low-moderate quality of evidence. We discuss recommendations to optimize PPI therapy and reduce risks by adjusting duration of therapy and dosage, as well as prophylactic measures and lifestyle modifications. Patients and clinicians will have a better understanding on optimizing PPI therapy for different rheumatological conditions in both the short and long-term setting.