More than two decades have been spent to develop many families of synthetic matrix metalloproteinases inhibitors (MMPI) as therapeutical agents for serious pathologies. Unfortunately, clinical trials conducted on broad-spectrum inhibitors have yielded disappointing results, especially in the cancer pathology area. Despite these outcomes, some small synthetic MMPI are in advanced trials or launched in clinical ones for cancer, arthritis, periodontal diseases. Today many groups are developing intensive efforts to find new classes of inhibitors characterized by improved potency and, above all, high selectivity against the specific MMP involved in each targeted pathology. The new challenges include the development of new MMPI bearing more effective ZBGs and the development of new allosteric non-zinc binding inhibitors, devoid of ZBGs. An analysis of more recent results in this field reported on journals and patents will be developed, to consider some of the more interesting new highly selective synthetic MMPI, their SARs, the new theoretical approaches used for modelling and the results of their biological evaluations.