Chemotherapy for the treatment of pancreatic carcinoma is clearly evolving. Recent studies have provided the first evidence in more than a decade that combining gemcitabine with another systemic agent can improve outcome over that achieved with standard gemcitabine monotherapy in patients with advanced disease. Particularly promising are the gemcitabine/capecitabine (Gem-Cap) combination, which showed a significant survival benefit over single-agent gemcitabine in a large phase III study; gemcitabine/oxaliplatin combinations, some of which use a modulated gemcitabine infusion schedule; and gemcitabine-based combinations with targeted therapies, based on a significant survival benefit achieved with gemcitabine plus the epidermal growth factor receptor inhibitor erlotinib in the phase III setting, as well as encouraging phase II results with cetuximab and bevacizumab. Further advances will probably be made with combinations of targeted therapies. Better understanding of the carcinogenesis of this very aggressive cancer is also needed.