Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by dismal prognosis. Late diagnosis, resistance to chemotherapy, and lack of efficacious targeted therapies render PDAC almost untreatable. Dysregulation of splicing, the process that excises the introns from nascent transcripts, is emerging as a hallmark of PDAC and a possible vulnerability of this devastating cancer. Splicing factors are deregulated in PDAC and contribute to all steps of tumorigenesis, from inflammation-related early events to metastasis and acquisition of chemoresistance. At the same time, splicing dysregulation offers a therapeutic opportunity to target cancer-specific vulnerabilities. We discuss mounting evidence that splicing plays a key role in PDAC and the opportunities that this essential process offers for developing new targeted therapies.