The management of acid-based disorders was transformed in the 1980s with the advent of proton pump inhibitors (PPIs), which target the hydrogen-potassium adenosine triphosphatase (proton pump) of the parietal cell. Potassium-competitive acid blockers (P-CABs), a newer class of medications, act at the same proton pump through a novel mechanism resulting in profound and sustained acid suppression. Although trials in Asian populations over the past decades have highlighted the potential benefit of P-CABs, clinical trials in Western populations have been initiated more recently. These trials evaluated vonoprazan in patients with infection, erosive esophagitis, and heartburn with nonerosive reflux disease and have demonstrated promising results, culminating in US Food and Drug Administration approval for these indications. Adverse event profiles between PPIs and P-CABs appear comparable thus far, although additional long-term data on P-CABs are needed. While navigating the evolving landscape of acid suppression, it is crucial to identify which patients and diseases are poised to derive the most benefit from this emerging therapeutic option. This article seeks to highlight important pharmacologic properties of PPIs and P-CABs, understand the current literature with a focus on clinical trials in Western populations, and explore potential scenarios for integrating P-CABs into therapeutic regimens.