The skin is the largest organ of the body and protects the organism against external physical, chemical and biological insults, such as wounding, ultraviolet radiation and micro-organisms. The epidermis is the upper part of the skin that is continuously renewed. The keratinocytes are the major cell type in the epidermis and undergo a specialized form of programmed cell death, called cornification, which is different from classical apoptosis. In keep with this view, several lines of evidence indicate that NF-kB is an important factor providing protection against keratinocyte apoptosis in homeostatic and inflammatory conditions. In contrast, the hair follicle is an epidermal appendage that shows cyclic apoptosis-driven involution, as part of the normal hair cycle. The different cell death programs need to be well orchestrated to maintain skin homeostasis. One of the major environmental insults to the skin is UVB radiation, causing the occurrence of apoptotic sunburn cells. Deregulation of cell death mechanisms in the skin can lead to diseases such as cancer, necrolysis and graft-versus-host disease. Here we review the apoptotic and the anti-apoptotic mechanisms in skin homeostasis and disease.