Using infrared and Raman microspectroscopy, the authors examined the interaction of cold atmospheric plasma with the skin’s built-in protective cushion, the outermost skin layer stratum corneum. Following a spectroscopic analysis, the authors could identify four prominent chemical alterations caused by plasma treatment: (1) oxidation of disulfide bonds in keratin leading to a generation of cysteic acid; (2) formation of organic nitrates as well as (3) of new carbonyl groups like ketones, aldehydes and acids; and (4) reduction of double bonds in the lipid matter lanolin, which resembles human sebum. The authors suggest that these generated acidic and NO-containing functional groups are the source of an antibacterial and regenerative environment at the treatment location of the stratum corneum. Based upon the author’s results, the authors propose a mechanistic view of how cold atmospheric plasmas could modulate the skin chemistry to produce positive long-term effects on wound healing: briefly, cold atmospheric plasmas have the potential to transform the skin itself into a therapeutic resource.