Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Radical surgery represents the only curative treatment and in resectable PDAC surgery, followed by adjuvant chemotherapy, is currently the standard of care. Unfortunately, also in clearly resectable cancers, the prognosis remains poor, mainly due to the rapid occurrence of local or systemic relapse and the impact of frequent post-operative complications remains one of the greatest issues on the administration of adjuvant therapy. Neoadjuvant and peri-operative multimodal treatment have demonstrated in some gastro-intestinal cancers, like oesophagus and gastric cancer, their efficacy in prolonging survival in many phase III randomized trials. We can speculate a similar effectiveness also in the PDAC, even if at present equally solid data are missing. Recommended guidelines for neoadjuvant systemic therapy exist only for borderline-resectable and/or locally advanced disease. Concerning resectable disease, there are only retrospective studies and phase II prospective data. Most of these trials include concurrent radiotherapy and chemotherapy, employing only gemcitabine or fluoropyrimidines. Current and future studies could better explain the role of modern radiotherapy techniques and polychemotherapy schemes that have demonstrated efficacy in advanced and adjuvant setting. This review summarizes the current literature, with particular regard to still open questions and ongoing trials.