Oesophageal cancer (OC), is an aggressive cancer constituting a major cause of cancer-related deaths worldwide. Recent advances in surgical techniques, incorporation of new therapeutic approaches -- adjuvant/neoadjuvant chemoradiotherapy -- and integration of new cytotoxic drugs into the management of oesophageal cancer have increased the response rate percentages to 40-50%, with minor impact on the overall survival. The need for an efficacious therapy with minimal toxicity along with a better understanding of molecular pathways of oesophageal carcinogenesis has led to the development of novel anticancer agents. These agents have targeted mechanisms of action such as: (1) inhibitors of the ErbB receptor family, (2) vascular endothelial growth factor (VEGF) inhibitors, (3) selective inhibitors of cycloxygenase-2, (4) matrix metalloproteinase inhibitors, (5) cell-cycle regulators, and (6) promoters of apoptosis. The incorporation of these agents into combined modality treatment schedules for advanced and early stage tumors together with the identification of patients who will most likely benefit will provide novel opportunities in the treatment of oesophageal cancer.