Pancreatic ductal adenocarcinoma is one of the deadliest cancers, with its incidence on the rise. Major challenges in overcoming the poor prognosis presented by this disease lies in late detection and the aggressive biology of the disease. Intra-tumoral heterogeneity, presence of a robust, reactive and desmoplastic stroma as well as the crosstalk between the different tumor components indicate that a complete understanding of the pancreatic tumor biology is required to better understand the therapeutic challenges posed by this disease.