Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality with poor survival outcomes. Resection is the sole definitive management; however, most PDAC are diagnosed with unresectable disease including metastatic, locally advanced (LAPC) or borderline resectable (BRPC). Recently, neoadjuvant therapy has demonstrated potential in downstaging these tumours for resection. This literature review explores current and novel approaches in the management of BRPC and LAPC. Methods: A systematic search of Medline, Embase, Cochrane Central and Emcare databases was conducted. Inclusion criteria were primary articles that explore current and novel therapies that led to downstaging of BRPC and LAPC to resection, resection outcomes and oncological outcomes associated with this. Results: 86 studies were included in the review. Neoadjuvant regimens incorporating chemotherapy or radiotherapy, whether sequential or concurrent, demonstrated the greatest performance in terms of tumour responses, rates of proceeding to surgery, R0 and N0 status, and oncological outcomes including overall survival, recurrence-free survival, progression-free survival and recurrence rates. While there is a paucity of studies exploring novel treatments including neoadjuvant irreversible electroporation, targeted therapy, and immunotherapy, promising results have been reported. Conclusion: PDAC continues to contribute to cancer-related mortality and the mortality from PDAC is expected to rise. This underscores the significance of neoadjuvant approaches in the management of BRPC and LAPC. This review emphasises the importance of neoadjuvant therapy, both current and novel with surgical resection, which warrant further investigation in future clinical trials. These new approaches to neoadjuvant modalities can potentially inform guidelines and practices to optimise the management of BRPC and LAPC.