This perspective on Stratton et al. (beginning on p. 160), Kowalczyk et al. (beginning on p. 170), and Katiyar et al. (beginning on p. 179) highlights the common theme of translational investigation of natural substances and their molecular effects and mechanisms in preventing skin squamous cell carcinoma, which has potentially severe clinical consequences. These studies comprise results of naturally occurring phytochemicals and green tea polyphenols in mouse models of UV-induced and chemically induced skin carcinogenesis and results of perillyl alcohol in a phase IIa clinical trial-all pointing to the great promise of this exciting approach for better understanding of and preventing skin cancer.