Capsaicin is a principal pungent ingredient in hot peppers, which are consumed worldwide. Capsaicin has been shown to induce cancer cell death, and it has also been suggested that capsaicin may act as a carcinogen or cocarcinogen during the promotion stage of cancer. Hwang and colleagues show that capsaicin has a cocarcinogenic effect on TPA-promoted skin carcinogenesis in vivo that is mediated through the epidermal growth factor receptor (EGFR) and not the transient receptor potential vanilloid subfamily member 1 (TRPV1). Significantly, topical application of capsaicin on the dorsal skin of wild-type or TRPV1 knockout mice induced more and larger skin tumors in the knockout mice, suggesting that capsaicin acts through a TRPV1-independent mechanism. Notably, cyclooxygenase-2 (COX-2) expression was highly elevated with capsaicin treatment in TRPV1 knockout mice, and inhibitors of EGFR/MEK signaling suppressed capsaicin/TPA–induced COX-2 expression. These results raise concerns that a natural compound found in hot peppers used in over-the-counter topical pain remedies may heighten skin cancer risk by affecting EGFR-dependent signaling. For details, see the article by Hwang and colleagues on page 6859 of this issue.