Degradation of DNA is involved in key processes maintaining the integrity of the epidermis such as the cornification of keratinocytes, the removal of damaged cells and the defense against potentially harmful microorganisms. Recent studies have characterized some of the molecular mechanisms and physiological functions of DNA degradation in the epidermis. Deoxyribonuclease (DNase)1L2 and TREX2 were identified as epidermis-specific DNases and DNase 2 was shown to be the predominant DNA-degrading enzyme on the surface of the skin. Here we review the latest insights into the DNA catabolism in the skin and discuss open questions pertaining to the molecular biology of epidermal DNA breakdown.