Pancreatic cancer (PC) is the fourth leading cause of cancer death in Western societies with an overall 5-year survival rate of 8%. Despite significant recent efforts into developing novel therapeutics, gemcitabine and nab-paclitaxel chemotherapy remains the standard-of-care for patients with advanced PC, despite imparting only a marginal overall survival advantage of 1.8 months. Extensive molecular heterogeneity of PC, few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. Itraconazole is an inexpensive, safe, orally administered and clinically used anti-fungal agent, recently shown to possess anti-cancer activities in a range of malignancies including lung, prostate and ovarian cancer (Aftab et al. 2011; Antonarakis et al. 2013). Despite the lack of preclinical studies of itraconazole in PC, there are several remarkable case-reports and retrospective studies suggesting significant efficacy (Tsubamoto et al. 2015; Lockhart et al. 2015). Here we aim to explore the potential therapeutic benefit of itraconazole and rationally-designed combination therapies in vitro and in vivo utilising our robust and well-characterised patient-derived xenograft (PDX) and cell line (PDCL) models of PC. In vitro, PDCLs exhibited a diverse range of sensitivities to itraconazole, and sensitive lines (IC50<5µM) displayed strong synergism when treated with itraconazole in combination with gemcitabine chemotherapy. Data also suggest a correlation of itraconazole sensitivity with NPC1 receptor expression in our PDCLs, which may warrant further investigation of NPC1 as a potential biomarker of response (Head et al. 2015). In vivo, combination of itraconazole and chemotherapy significantly reduced tumour burden and improved overall survival in a KPC mouse model of PC. Our findings demonstrate the potential efficacy of repurposing itraconazole as a cheap and safe complement to chemotherapy in PC, a molecularly varied disease in dire need of tailored and effective treatment strategies.