Simple SummaryPancreatic cancer has one of the worst prognoses among all the malignancies. To date, there are no effective strategies for preventing, diagnosing, or treating this aggressive disease. Increasing evidence shows that the human microbiome influences pancreatic cancer development and the response to treatment, which is the main aim of this review. Future studies will be key to determining whether or not this knowledge might be used to develop new strategies that harness the microbiome for diagnostic and therapeutic interventions in pancreatic cancer.AbstractPancreatic cancer mortality is expected to rise in the next decades. This aggressive malignancy has a dismal prognosis due to late diagnosis and resistance to treatment. Increasing evidence indicates that host–microbiome interactions play an integral role in pancreatic cancer development, suggesting that harnessing the microbiome might offer promising opportunities for diagnostic and therapeutic interventions. Herein, we review the associations between pancreatic cancer and the intratumoral, gut and oral microbiomes. We also explore the mechanisms with which microbes influence cancer development and the response to treatment. We further discuss the potentials and limitations of using the microbiome as a target for therapeutic interventions, in order to improve pancreatic cancer patient outcomes.