Pancreatic cancer(PC) would become the second leading cause of cancer death in the near future, despite representing only 3% of new cancer diagnosis. Survival improvement will come from a better knowledge of risk factors, earlier diagnosis, better integration of locoregional and systemic therapies, as well as the development of more efficacious drugs rising from a deeper understanding of disease biology. For patients with unresectable, non-metastatic disease, combined strategies encompassing primary chemotherapy and radiation seems to be promising. In fit patients, new polychemotherapy regimens can lead to better outcomes in terms of slight but significant survival improvement associated with a positive impact on quality of life. The upfront use of these regimes can also increase the rate of radical resections in borderline resectable and locally advanced PC. Second line treatments showed to positively affect both overall survival and quality of life in fit patients affected by metastatic disease. At present, oxaliplatin-based regimens are the most extensively studied. Nonetheless, other promising drugs are currently under evaluation. Presently, in addition to surgery and conventional radiation therapy, new locoregional treatment techniques are emerging as alternative options in the multimodal approach to patients or diseases not suitable for radical surgery. As of today, in contrast with other types of cancer, targeted therapies failed to show relevant activity either alone or in combination with chemotherapy and, thus, current clinical practice does not include them. Up to now, despite the fact of extremely promising results in different tumors, also immunotherapy is not in the actual therapeutic armamentarium for PC. In the present paper, we provide a comprehensive review of the current state of the art of clinical practice and research in PC aiming to offer a guide for clinicians on the most relevant topics in the management of this disease. Pancreatic cancer (PC) would become the second leading cause of cancer death in the near future, and even representing only 3% of new cancer diagnosis. Survival improvement will come from a better knowledge of risk factors, earlier diagnosis, better integration of locoregional and systemic therapies, as well as the development of more efficacious drugs rising from a deeper understanding of disease biology. For patients with unresectable, non-metastatic disease, combined strategies encompassing primary chemotherapy and radiation seems to be promising. In fit patients, new polychemotherapy regimens can lead to better outcomes in terms of slight but significant survival improvement associated with a positive impact on quality of life. The upfront use of these regimes can also increase the rate of radical resections in Borderline resectable and locally advanced PC. affect both overall survival and quality of life in fit patients affected by metasta At present, oxaliplatin-based regimens are the most extensively studied. Nonetheless, other promising drugs are currently under evaluation. Presently, in addition to surgery and conventional radiation therapy, new locoregional treatment techniques are emerging as alternative options in the multimodal approach to patients or diseases not suitable for radical surgery. As of today, in contrast with other types of cancer, targeted therapies failed to show relevant activity either alone or in combination with chemotherapy and, and, current clinical practice does not include them. Up to now, despite the fact of Extreme promising results in different tumors, also immunotherapy is not in the actual therapeutic armamentarium for PC. In the present paper, we provide a comprehensive review of the current state of the art of clinical practice and research in PC aiming to offer a guide for clinicians on the most relevant topics in the management of this disease.