Pancreatic ductal adenocarcinoma (PDA) has become one of the leading causes of cancer-related deaths across the world. A lack of durable responses to standard-of-care chemotherapies renders its treatment particularly challenging and largely contributes to the devastating outcome. Gemcitabine, a pyrimidine antimetabolite, is a cornerstone in PDA treatment. Given the importance of gemcitabine in PDA therapy, extensive efforts are focusing on exploring mechanisms by which cancer cells evade gemcitabine cytotoxicity, but strategies to overcome them have not been translated into patient care. Here, we will introduce the standard treatment paradigm for patients with PDA, highlight mechanisms of gemcitabine action, elucidate gemcitabine resistance mechanisms, and discuss promising strategies to circumvent them.