Proton pump inhibitors (PPIs) are commonly used to treat acid-related diseases, most notably gastroesophageal reflux disease. PPIs are designed to shut down the gastric proton pump (H+/K+-ATPase) of parietal cells, thereby raising the pH of the stomach. While effective, a number of side effects have been associated with PPI use. Naturally occurring bacteria, some of which are acid-producing and contain ATPase enzymes, have also been found within the stomach, upper gastrointestinal tract, and oral cavity. Likewise, a number of fungi are known to inhabit the human body; some of these fungi contain H+-ATPase enzymes. Recent literature has suggested that PPIs may be inadvertently affecting these bacteria and fungi in two different ways: 1) PPIs may directly target the proton pumps of the bacteria and fungi, and/or 2) PPIs may indirectly affect the microenvironment of the flora via changes in pH. These unintended interactions are exasperated by the systemic distribution of PPIs throughout the body and may potentially lead to some of the side effects observed with PPI use. Herein we summarize what is currently known about the interactions between the PPIs and the natural human microbiota.