Nanoparticles and nanomaterials (NPs), owing to their small size, can interact with the skin and penetrate and permeate the skin with higher efficiency compared to bulk materials. Their effect can be local, causing irritation or sensitization, and general, causing permeation through the skin, reaching derma, and systemic circulation. Metal nanoparticles can release metal ions that can elicit allergic contact dermatitis when sensitizing metals are present, such as nickel, cobalt, and chromium. NPs containing toxic agents such as Cd or As can cause acute or chronic systemic exposure. In the case of damaged skin, NPs absorption can increase significantly. Moreover, ZnO and TiO2 are widely used in sunscreens to protect the skin from sunburns, and some metal nanoparticles, mainly gold, have been suggested alone or as drug carriers to treat skin inflammatory diseases and cancer. Many nanoparticle formulations have been studied for rejuvenation treatments because of the enhanced penetration of active products owing to their small size. Finally, the use of an emollient cream with or without a chelating agent can be effective, together with protective gloves, in preventing metal nanoparticle skin penetration during the handling of nanoparticles.