Proton pump inhibitors (PPIs) have fundamentally improved the treatment of diseases associated with excessive production of stomach acid.[1] However, widespread and long-term use of PPIs has raised concerns about potential side effects, including the risk of upper gastrointestinal cancer.[1] In research commented in the journal PLOS Medicine, the authors used a large national database in Israel, identified 875 cases of upper gastrointestinal cancer and compared them with 8,750 controls.[1] In the analysis, they took into account the reason for the PPI prescription and assessed exposure at different time periods before the cancer diagnosis to limit bias and so-called reverse causality.[1] They found that cancer risk gradually decreased with increasing time since last PPI use and did not observe an increased risk for PPI use more than a year before diagnosis.[1] These results suggest that previously reported associations between long-term PPI use and upper gastrointestinal cancer likely resulted mainly from biases in older observational studies.[1] At the same time, the authors point out that possible biological mechanisms (e.g. changes in gastrin levels and gastric microbiota) must be considered in a wider global and clinical context.[1]