Cyclooxygenase (COX) and nitric oxide synthase (NOS) are two isoenzyme families that both implicated in the inflammatory process. Indeed, the activities of both enzymes are so important that two of the most important classic drugs, Aspirin and Nitroglycerin, are directly related to the COX pathway and NO pathway, respectively. Although Aspirin has been used as an anti-inflammatory drug since 1876, it was not until 1970s that its action has been shown to be involved in inhibition of the Cox enzyme, being a class of drugs known as non-steroidal anti-inflammatory drugs(NSAIDs). This signaling pathway has led to extensive research led by a number of pharmaceutical companies in the race to make more effective anti-inflammatory drugs, such as ibuprofen and colecoxib to name but a few. Similarly, the nitroglycerin has been used to treat angina more than a hundred years, its only until late 1980s its drug action by releasing nitric oxide gas have been recognized. There are not however, many anti-inflammatory drugs that specially target NOS or more specifically, iNOS, although there are various studies and trial that are investigating the effect of iNOS inhibition in various inflammatory conditions such as sepsis and other chronic illness including cancer. More recently, COX pathway has been found to be regulated by NO pathway and therapeutic potentials of NO-releasing aspirin hybrid drugs has been developed. In this review, we will discuss both pathways and their cross talk and pharmaceutical potentials for future therapeutic development based on these signaling transduction pathways.