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New therapeutic strategies are needed to improve the outcome and the quality of life for pancreatic cancer (PC) patients. This study aimed to investigate new treatment strategies for PC by assessing the potential role of retinoids and epigenetic drugs both in vitro and in an animal model of PC. Aberrant retinoid signaling is associated with carcinogenesis, and has been identified in PC. The role of key retinoid signaling components implicated in retinoid resistance, CRBP1, RARα and RARB, were investigated. CRBP1 expression was downregulated in the majority of PC cell lines and human samples. Re-expression of epigenetically silenced CRBP1 in MiaPaCa2 cells, which are resistant to retinoid treatment, did not increase the sensitivity of these cells to retinoid treatment. We demonstrated that the normal pancreatic cell line, HPDE, was sensitive to retinoid treatment and did not express RARB due to epigenetic silencing, while concomitant loss of RARα function did not reduce retinoid sensitivity in these cells. The effect of a K-ras point mutation in inducing aberrant retinoid signaling in PC was also investigated, as treatment with inhibitors of K-ras activity has been reported to diminish retinoid-induced differentiation in other cancers. However, a reduction in retinoid sensitivity was not observed in HPDE cells harboring mutant K-ras. These data suggest that CRBP1, RARα, RARB and the K-ras point mutation are unlikely to initiate retinoid resistance in PC. Combination treatment with epigenetic drugs, Histone Deacetylases inhibitors (SAHA and TSA) and/or DNA Methyltransferase Inhibitors (5-AZA-dc), decreased MiaPaCa2 cell proliferation and induced cell cycle arrest in vitro. The efficacy of 5-AZA-dc and SAHA was examined in a PC mouse model, which demonstrated that epigenetic treatment significantly increased the tumour Lag period but did not decrease the tumour growth rate. This suggests that epigenetic therapy alone may not be effective for the treatment of PC in vivo but may be more effective in combination with chemotherapeutic agents. Further studies are necessary to elucidate the mechanisms by which PC remains resistant to retinoid-based therapies, and to design and implement a more targeted delivery system to combat this devastating disease.