Pancreatic ductal adenocarcinoma has a high mortality rate, which is generally related to the initial diagnosis coming at late stage disease combined with a lack of effective treatment options. Gemcitabine has been the most commonly used drug over the past decade and is still the cornerstone of therapy in adjuvant and metastatic settings. Intrinsic or acquired resistance of tumours to gemcitabine is, however, a major clinical problem. New therapeutic strategies are urgently needed whereas we also need to identify new prognostic and predictive biomarkers. This article focuses on gemcitabine resistance, on the role of chemokines and chemokine receptors in pancreatic carcinoma initiation and progression, and on stellate cells as partners in crime with neoplastic epithelial cells.