Pancreatic cancer is an exceptionally devastating and incurable disease, the treatment of which has largely been unsuccessful due to the higher resistance of pancreatic tumor cells to oncologic treatment. PDAC cells have accumulated different molecular mechanisms, which enable survival against cytotoxic therapies. Defects of the apoptosis pathway play a crucial role. For the last 10 years, many investigations were underway to get insights into the details of the anti-apoptotic mechanisms of PDAC cells. The present review provides a comprehensive description of the molecular signaling of the apoptotic pathway, an incentive on the potential pathogenetic role of different molecular defects on existing oncologic treatments and an appraisal of the most recent therapeutic strategies applied at a cell biochemical level.