Five decades of extensive research have passed since the description for the first time of the existence of an enzyme, which had the ability to degrade collagen during the metamorphosis of tadpoles. In fact, during these years, a large family of enzymes possessing the unique ability of degrading the extra cellular matrix (ECM) has been discovered. These enzymes are widely known as Matrix Metalloproteinases (MMPs) and it is noteworthy that many members of this family are directly linked to several human diseases such as arthritis and cancer. Moreover, due to the critical role of certain members of MMPs in cancer invasion and metastasis, great efforts have been made in order to find new inhibitory compounds against these MMPs. In this work we attempt to summarize the current status of the intervention strategies against MMPs, using inhibitory compounds that could block the activation of MMPs directly or indirectly. Furthermore we will try to shed light towards new potential strategies of MMP inhibitors using monoclonal antibodies.