The claimed invention provides highly specific and sensitive methods for in vivo, in vitro, or ex vivo imaging of specific extracellular protease activity using an anthrax binary toxin system. The system targets cells that express extracellular proteases of interest. Such a system would be highly useful since various studies have demonstrated a positive correlation between the activity of extracellular proteases and various diseases and undesirable physiological conditions. For example, breakdown of the extracellular matrix by extracellular proteases is a prerequisite for the invasive growth of malignant cells, metastatic spread of tumors, and other pathological remodeling of tissue. In this case, methods are provided for the imaging of a specific extracellular protease by contacting a cell with: 1) a mutant anthrax toxin protective antigen (mPrAg) that binds to a cell surface receptor of a cell expressing an extracellular protease and is cleaved by a specific extracellular protease expressed by the cell and 2) a ligand that specifically binds to the cleaved mPrAg and is linked to a moiety that is detected by an imaging procedure, thereby forming a ligand-mPrAg complex that is translocated into the cell. The detectable moiety linked to the ligand in the ligand-mPrAg complex can be imaged before, during, or after translocation. Specific disease examples might include, but are not necessarily limited to, cancer, inflammation, and tumor progression or regression.