MDM2 protein negatively regulates p53 and is found to be elevated in cancer cells. An attractive approach towards targeting MDM2 is the use of small molecule inhibitors that bind to MDM2 and disrupt the MDM2-p53 interaction. Our laboratory has been at the forefront in testing MDM2 inhibitors in pancreatic adenocarcinoma (PaCa), a deadly disease with approximately 50% wild-type p53 population. Emerging evidence suggests that apart from regulating p53, MDM2 can influence other key molecules involved in cancer. This review summarizes recent advancements in the development of MDM2 inhibitors, their novel primary and secondary targets and highlights their potential as therapeutics for PaCa.