Pancreatic cancer remains the fourth leading cause of cancer deaths in males and females in the beginning of this new millennium. The 5-year survival for all stages remains less than 5%. The frequent diagnosis at late stages of the disease limits the role of surgery as a curative modality in pancreatic cancer. Despite recent advances, systemic treatment continues to have a limited role in the adjuvant setting, and chemotherapy is mostly palliative in advanced and metastatic pancreatic cancer patients. The differential diagnosis of pancreatic cancer and other gastrointestinal malignancies is, many times, challenging. Advances in the understanding of the disease biology may help in better diagnosis and treatment approaches. Clinical trials with molecular targeting agents are starting to emerge.