Almost 90 years have passed since Alexander Fleming discovered the antimicrobial activity of lysozyme, the first natural antibiotic isolated from our body. Since then, various types of molecules with antibiotic activity have been isolated from animals, insects, plants, and bacteria, and their use has revolutionized clinical medicine. So far, more than 1,200 types of peptides with antimicrobial activity have been isolated from various cells and tissues, and it appears that all living organisms use these antimicrobial peptides (AMPs) in their host defense. In the past decade, innate AMPs produced by mammals have been shown to be essential for the protection of skin and other organs. Their importance is because of their pleiotrophic functions to not only kill microbes but also control host physiological functions such as inflammation, angiogenesis, and wound healing. Recent advances in our understanding of the function of AMPs have associated their altered production with various human diseases such as psoriasis, atopic dermatitis, and rosacea. In this review, we summarize the history of AMP biology and provide an overview of recent research progress in this field.