The invention provides novel methods for identifying modulators of transmembrane protease serine 6 (TMPRSS6). The methods comprise screening test agents for ability to modulate proteolysis of a pathogenic toxin substrate or a synthetic peptide substrate of TMPRSS6. The methods can further comprise screening the identified modulating agents for ability to inhibit infections of pathogens. Also provide in the invention are methods and pharmaceutical compositions for treating infections of pathogens whose toxins are proteolytically activated by TMPRSS6.