One of the largest hurdles to the efficacy of cancer therapeutics, and a main cause of relapse, is therapy resistance. In response, researchers have developed model systems to better understand therapy resistance. Cancer research employs several model systems that reflect the biology of actual human tumors: in vitro models (2D, 3D cell cultures), in vivo models (PDX, GEMMS, transgenic), proteomic models, and computational or mathematical models. One cancer that has been extensively modeled is pancreatic ductal adenocarcinoma (PDAC). PDAC is the third most common cause of annual cancer deaths in developed countries; as its incidence and mortality rates continue to increase, PDAC is projected to be the second leading cause of cancer deaths by 2030. Although chemotherapy is a pillar of clinical PDAC treatment, its outcome typically leads to multi-drug resistance, drastically restricting the curative effect of drugs for a variety of tumors. Elucidating the underlying mechanisms for resistance through different models is essential for the development of new strategies and therapies. This review provides insight into the range of in vitroand in vivo models of pancreatic cancer used in preclinical research. This paper provides an overview of platforms for cancer research with a focus on those devoted to resistance mechanisms in PDAC and to the primary therapeutic intervention for PDAC, gemcitabine (GEM).