Background Neoadjuvant therapies (neoTx) have revolutionized the treatment of borderline resectable (BR) and locally advanced (LA) pancreatic cancer (PCa) by significantly increasing the rate of R0 resections, which remains the only curative strategy for these patients. However, there is still room for improvement of neoTx in PCa. Purpose Here, we aimed to critically analyze the benefits of neoTx in LA and BR PCa and its potential use on patients with resectable PCa. We also explored the feasibility of arterial resection (AR) to increase surgical radicality and the incorporation of immunotherapy to optimize neoadjuvant approaches in PCa. Conclusion For early stage, i.e., resectable, PCa, there is not enough scientific evidence for routinely recommending neoTx. For LA and BR PCa, optimization of neoadjuvant therapy necessitates more sophisticated complex surgical resections, machine learning and radiomic approaches, integration of immunotherapy due to the high antigen load, standardized histopathological assessment, and improved multidisciplinary communication.