Antimicrobial peptides (AMPs), known as “natural antibiotics”, are the first line of defense in humans as effector molecules of the innate immune system of the skin. They present activity against a broad spectrum of bacteria, fungi, parasites and enveloped viruses. An increasing number of studies report altered expression of AMPs in human cancers. Antimicrobial peptides such as human β defensins, human cathelicidin, ribonuclease 7 and psoriasin, a member of S100 proteins, are suggested to play a role in tumor progression and tumor suppression in pre-malignant skin lesions and malignancies. Noticeable changes in AMPs expression in skin tumorigenesis suggest a correlation between peptides and cutaneous cancers, though it is still a matter of discussion. In this article we review recent studies on the relationship between antimicrobial peptides and skin tumorigenesis.