Among various matrix metalloproteinases (MMPs), MMPs having medium-size S1' pockets are established as promising biomolecular targets for executing crucial roles in cancer, cardiovascular diseases, and neurodegenerative diseases. However, no such MMP inhibitors (MMPIs) are available to date as drug candidates despite a lot of continuous research work for more than three decades. Due to a high degree of structural resemblance among these MMPs, designing selective MMPIs is quite challenging. However, the variability and uniqueness of the S1' pockets of these MMPs make them promising targets for designing selective MMPIs. In this perspective, the overall structural aspects of medium-size S1' pocket MMPs including the unique binding patterns of enzyme-inhibitor interactions have been discussed in detail to acquire knowledge regarding selective inhibitor designing. This overall knowledge will surely be a curtain raiser for the designing of selective MMPIs as drug candidates in the future.