Pancreatic ductal adenocarcinoma (PDAC) is a relatively rare tumor, however it is the seventh cancer related leading cause of death worldwide. Mean survival time after PDAC diagnosis is less than 1 year and the median survival of PDAC patients has hardly changed in the past 40 years. Until now, cytotoxic and/or targeted therapy produced disappointing results in the treatment of PDAC. Currently, surgical resection offers the only hope for survival, but it is suited for only 15% of PDAC patients. To complicate matters, the vast majority of PDAC patients relapse after surgery. Thus, there is a burning need to develop better therapeutic strategies for PDAC treatment. PDAC cells have adapted to survive and proliferate in a tumor microenvironment that is constitutively under deprivation of nutrients and oxygen, via mechanisms triggered by oncogenic KRAS. In this review, we highlight the metabolic alterations observed in PDAC, with a particular emphasis on past and ongoing strategies to develop inhibitors of KRAS effector signaling. This review provides an up to date information reported in the literature on the most relevant inhibitors of metabolism targets in PDAC. The review specifically provides an overall picture of the current state of the art with the aim of being thought provoking for plausible novel chemotherapeutic strategies of intervention. We anticipate that with our increased collective understanding of PDAC metabolic behavior, PDAC patients could hopefully benefit from these novel therapies.