The response to environmental cues such as inflammatory stimuli requires coordinated cellular functions. Certain proteins have functions on both sides of the plasma membrane to allow coordination between the extracellular and intracellular milieus. The membrane-anchored matrix metalloproteinase MT1-MMP is well positioned to sense and modify the extracellular environment by processing matrix components, transmembrane proteins and soluble factors. Recent findings show, however, that MT1-MMP also plays unexpected intracellular roles in macrophages through its location at the plasma membrane, the Golgi or the nucleus, impacting cell motility, metabolism and gene transcription. MT1-MMP is thus an example of the evolutionary diversification of protein function, allowing optimal coordination between extracellular stimuli and cellular responses. It remains to be determined whether these new MT1-MMP functions are specific to macrophages, professional phagocytes involved in inflammation, or are present in other inflammation-responsive cells. In this review, we will summarize these site-specific MT1-MMP functions in macrophages and comment on the possible conservation of these functions in endothelial cells.