Tremendous progress in pathogenic role of cyclooxygenase-2 (COX-2) in diverse cancers triggering the cancer research in the direction of COX-2 inhibitors. Several experimental studies reported overexpression of COX-2 in cancer cells. Mechanisms mediating the pathobiology of COX-2 in cancer are still unclear and needs to be clarified. However, recent studies have shown that the levels of COX-2 isoenzymes are elevated in certain cancers like colo-rectal carcinoma, squamous cell carcinoma of head and neck and certain cancers of lung and breast. Our review article aims to summarize the role of COX-2 in various types of cancer and mechanisms emerged from recent research and their interaction with other cytokines. It seems mechanisms mediating COX-2 and its role in each cancer may be different. In general, possible signaling from the lipids (prostaglandins) can inhibit apoptosis and increase proliferation, motility, and metastatic potential. Furthermore, under certain conditions COX-2 can contribute to angiogenesis. Even, COX-2 is found in lung cancer cells that are responsible for suppressing patients' immune systems and therefore contributing to the growth of lung cancer. COX-2 inhibitors are already in clinical trials for the prevention of colorectal, oral, skin, esophageal and non-small-cell lung cancers and for the treatment of cervical, prostate, and metastatic breast cancers. Heightened role of COX-2 in cancer prompts the pharmaceutical research to design new and safer COX-2 inhibitors to minimize the cardiovascular side effects and improves the treatment of cancer.