Background: Proton pump inhibitors (PPIs) are one of the most widely used drugs worldwide and are overprescribed in patients with cancer; there is increasing evidence of their effects on cancer development and survival. The objective of this narrative review is to comprehensively identify cancer medications that have clinically meaningful drug–drug interactions (DDIs) with PPIs, including loss of efficacy or adverse effects, and to explore the association between PPIs and cancer. Methods: A PubMed search of English language studies published from 1 January 2016, to 1 June 2021 was conducted. The search terms included “proton pump inhibitors,” “cancer,” “chemotherapy,” “immunotherapy,” “hormonotherapies,” “targeted therapies,” “tyrosine kinase inhibitors,” and “gut microbiome”. Recent and relevant clinical trials, meta-analyses, and reviews were included. Results: PPIs may have pro-tumor activity by increasing plasma gastrin levels or anti-tumor activity by inhibiting V-ATPases. However, their impact on cancer survival remains unclear. PPIs may decrease the efficacy of some antineoplastic agents through direct DDIs (e.g., some tyrosine kinase inhibitors, capecitabine, irinotecan, methotrexate). More complex DDIs seem to exist for immunotherapies with indirect interactions through the microbiome. PPIs worsen hypomagnesemia, bone loss, iron, and vitamin B12 deficiencies but may have a protective effect on the renal system. Discussion/Conclusions: PPIs may interact with the cancer microbiome and the efficacy of various antineoplastic agents, although only a few DDIs involving PPIs are clinically significant. Further pharmaco-epidemiological studies are warranted, but physicians should be aware of the potential consequences of PPI use, which should be dose appropriate and prescribed according to guidelines.