The nails have always been traditionally considered a mirror of a person’s general health. However, they are more frequently altered by environmental than by endogenous causes. A typical example of this frequent misconception applies to nail fragility, which is often thought to indicate vitamin deficiency, while it is mainly caused by excessive dryness due to contact with water and irritants. True nail signs of systemic diseases are indeed rare. Systemic drugs, especially of some categories, such as anticancer agents, retinoids, and antiretrovirals, frequently alter the nails. Nail changes may sometimes be severe and associated with symptoms, which require treatment interruption or dosage change. An adequate knowledge of drug side effects and their possible preventive and therapeutic measures may help to increase patient compliance with therapy.