Since their discovery as tissue remodeling enzymes over 50 years ago, the matrix metalloproteinases (MMPs) and the related ADAM and ADAMTS families have been identified as major contributors to human diseases, ranging from inflammatory diseases to neurodegeneration to cancer. Once viewed monolithically as bad actors in disease progression, they were collectively thought to be an ideal drug target, especially to prevent tumor invasion and metastasis or to block tissue destruction in chronic inflammatory conditions. However, early clinical trials with metalloproteinase inhibitors were unsuccessful for a number of likely reasons, the most prominent being a lack of appreciation for the more nuanced functions of individual metalloproteinases. Indeed, while some metalloproteinases may promote disease processes, we now understand that others act to protect against disease morbidity, facilitate repair, dampen inflammation, and support other beneficial functions, contraindicating the use of broad-spectrum inhibitors. Hence, a common goal in the field has been to discover specific functions of specific MMPs and how their activities and substrate interactions are controlled, with the aim of identifying specific deleterious activities that can be targeted with new, rational therapies. The aim of this GRC is to highlight the investigative advances dissecting both the good and bad functions of individual MMPs and the many ways their activities are controlled by endogenous mechanisms. Discussions will explore new directions for investigations and highlight how these fundamental discoveries can lead to the design of novel, specific metalloproteinase-targeted modulators for the treatment of human disease.