Pancreatic cancer, or pancreatic ductal adenocarcinoma (PDAC), is the fourth most common cause of cancer-related death and carries a dismal five-year survival rate of only 6%. Although our understanding of the molecular basis of the disease has improved over the past several decades, this increase in knowledge has not translated to improved therapeutics. PDAC is a highly heterogeneous disease, with a complex array of variable mutations, alterations of gene expression, and tumor subtypes. It is often unclear as to what is driving tumor progression and difficult to target candidate pathways. It has recently become evident that the Wnt/β-catenin pathway is one such network that drives PDAC initiation, growth and metastasis, and that this critical developmental signaling cascade has the potential to be therapeutically targeted. This dissertation examined the molecular mechanisms driving the Wnt/β-catenin pathway and evaluated compounds to inhibit it in in vitro and in vivo models of PDAC. Endogenous Wnt/β-catenin activity was found to be highly variable across PDAC cell lines and patient tumors, with WNT7B and SUMO2 identified as key activators and inhibitors of pathway activity, respectively. WNT7B activation of Wnt/β-catenin signaling mediated an anchorage-independent growth phenotype, suggesting that this pathway represents a rational target for pharmacologic manipulation. Accordingly, the CBP/β- catenin inhibitor ICG-001 effectively prolonged survival through induction of G1 arrest in PDAC models. However, ICG-001 inhibition of growth could not be attributed to effects on the Wnt signaling pathway, rather it acted through direct modulation of key regulators of G1/S transition. Alternatively, the vitamin D analog calcipotriol was investigated as a potential Wnt/β-catenin inhibitor. Calcipotriol inhibited PDAC proliferation and Wnt/β-catenin activity through upregulation of LDLRAP1 and destabilization of the Wnt co-receptor LRP6. Vitamin D receptor was also identified as a potential biomarker to predict and monitor response to vitamin D-based or Wnt/β-catenin-targeted therapeutics. This dissertation provided valuable insights towards mechanisms regulating PDAC aggressiveness and characterized compounds currently under clinical evaluation for the treatment of PDAC.