Skin is the largest organ of the human body that harbors a robust and versatile immune surveillance system. Whereas impaired immune function of the skin enables tumor growth, excessive immune activation results in different inflammatory diseases of the skin. HLA-G is a non-classical MHC class I molecule that was initially described to provide immunotolerogenic signals. In this context, HLA-G was mainly investigated as a mechanism that tumor cells employ to evade and inhibit host immune response. Expression of HLA-G in several inflammatory conditions in the skin implicated that the (dys)function of this molecule may also underlie excessive immune stimulation observed in these disorders. This review focuses on the functionality of HLA-G in the skin and summarizes available data obtained from studies performed in skin cancer and inflammatory dermatoses.