Introduction: Pancreatic ductal adenocarcinoma (PDA) is an invasive cancer of the exocrine pancreas with a 5-year survival rate (<8%), highlighting the need for new therapies to increase patient survivability and remission rates. Current treatment options with chemotherapeutics have yielded minimal success, warranting further research into targeting alternative pathways in tumour progression. The complex tumour microenvironment (TME) of PDA contributes significantly to tumorigenesis and may contain promising novel targets. The therapeutic potential of some known TME elements will be explored, namely hypoxia, MMPs, and TGF-β. These options each have their merits and differences, which are crucial to evaluate and assess the trajectory of PDA research in the future. Methods: A literature review was performed to summarize all available research on the different current therapeutic options and TME components that can be utilized for PDA treatment. The terms "hypoxia," "MMPs," and "TGF-β'' were used as keywords to search databases including Medline, Embase, and CINAHL. These were searched in combination with terms relevant to PDA and TME. Studies that were peer-reviewed and written in English were taken into consideration, with a focus on those that were published between 2017 and 2022. Results: Each TME element of hypoxia, MMPs, and TGF-β have specific distinctive targets of HIF-1α, TIMP-1, and SMAD-independent pathways, respectively. These present varying mechanisms of action which differ in their efficacies and limitations. Several of these therapies are currently undergoing clinical trials to better understand the role of each inhibitor. Discussion: This literature review provides insight into the current and future treatments for PDA. Exploiting the TME to develop therapeutic interventions presents a promising strategy to inhibit disease progression, yet research done in PDA is still preliminary due to the disease complexity, but it is moving towards a clinical settings. Conclusion: Accumulating evidence has suggested that several opportunities for targeted therapy in the PDA TME are very promising and not yet thoroughly investigated. This review aids in accessibility by summarizing important information regarding PDA and the necessary further research into targeting the TME to develop a novel therapeutic treatment.