In 1994, the U. S. Army initiated a research effort towards an effective material that acts both as a protective barrier and as an active destructive matrix against chemical warfare agents (CWA). We report results on our preparation and evaluation of Reactive Topical Skin Protectants (rTSP's). These creams are composite materials consisting of a base material (TSP) and a reactive moiety. Using an established base of perfluorinated-polyether and perfluoropolyethylene solids we incorporated over 60 reactive components. Classes tested include organic polymers, organic/inorganic hybrid materials, polyoxometallates (POM's), enzymes, inorganic oxides, metal alloys and small molecules. We characterized these materials by light microscopy and FTIR. We determined the efficacy of these materials against both sulfur mustard (HD) and a representative nerve agent, soman (GD), using a penetration cell model coupled to a continuous air monitor and also by in vivo testing. Composite materials with optimum reactive compounds exhibit a 94% reduction of GD vapor break-through after 20 hours (from 9458 ng to 581 ng) and a 3.6 fold increase (from 162 min to 588 min) in the time 1000 ng of GD liquid penetrates through the material. Similar composite materials show a 99% reduction in HD vapor break-through after 20 hours (from 4040 ng to 16 ng), a 2.3 fold increase (from 524 min to >1200 min) in the time 1000 ng of HD vapor penetrates through the material, and an elimination of erythema versus control in an HD vapor challenge. These results indicate that an rTSP that protects against sulfur mustard and nerve agents is within reach.