The skin is often introduced as the largest organ of the human body which – being uniquely exposed to external stress – faces several types of challenges, from physical, chemical, biological, and immunological origin. Therefore, the skin is also a site where inflammation, oxidative stress and cellular damage occurs regularly. Heme oxygenase (HO), primarily functioning in the catabolism of heme, is a very important cytoprotective enzyme that has antioxidant, anti-inflammatory and anti-apoptotic properties. Given the need for an enzyme with such a combination of attributes in the skin, it is not surprising that HO is involved in physiological processes as well as pathological conditions of the skin. In the recent decade, a huge effort was undertaken to identify treatments that modify HO-activity for the treatment of inflammatory or malignant skin diseases. In this review, we highlight the role of HO in the skin in physiological conditions as well as in relevant dermatological diseases such as atopic dermatitis, psoriasis and melanoma.