Synthesis of a portion mixing library of putative inhibitors in a resin already containing a good fluorescence-quenched substrate, which may have been defined with substrate libraries as described in Chapter 8, provides a method for direct detection of inhibitory activity (1). Beads containing potential inhibitors remained dark while enzyme cleaved the substrate in beads containing noninhibitors, resulting in a dramatic increase in fluorescence. The dark beads can be collected and analyzed by sequence analysis.