Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor outcome. The presence of a dense desmoplastic stroma is a hallmark of this malignancy, and abundant hyaluronic acid (HA) within this stroma is a common feature of PDAC. At the end of 2019, an HA-targeting drug, after initial promise, failed phase 3 clinical trials in PDAC. This failure in the face of such strong evidence for biological importance forces us to turn back to the research and seek a better understanding of HA biology in PDAC. Therefore, in this review, we reexamine what is known about HA biology, the methods used to detect and quantify HA, and the ability of the biological models in which HA has been investigated to recapitulate an HA-rich desmoplastic tumor stroma. The role of HA in PDAC relies on its complex interplay with a range of HA-associated molecules, which have not been as extensively investigated as HA itself. Therefore, using large genomic data sets, we cataloged the abundance and activity in PDAC of molecules that modulate HA synthesis, degradation, protein interactions, and receptor binding. Based on their association with clinical characteristics and individual patient outcomes, we suggest a small number of HA-associated molecules that warrant further investigation as biomarkers and drug targets.