Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth most common cause of cancer-related deaths in the United States. It has a poor prognosis and remains a difficulty to treat malignancy. Over the past several decades, significant efforts have been directed towards developing new approaches to enhance the efficacy of therapeutic regimens for PDAC treatment. In recent years, the measurement of serum carbohydrate antigen 19-9 (CA 19-9) has become one of the most validated and extensively used tumour biomarkers for PDAC. In particular, serum CA 19-9 levels have been explored as a validated tool to predict either the signs of disease progression or the response to treatment. However, despite its clinical relevance, the implications on diagnosis or accurately predicting tumour resectability, and monitoring disease symptoms in PDAC patients remains limited. This current review highlights the recent updates on the applicability of CA 19-9, its exploitation, and challenges in predicting the treatment efficacy and responses in PDAC patients.