The 3 major lice that infest humans are Pediculus humanus capitis (head louse), Pthirus pubis (crab louse), and Pediculus humanus humanus (body louse). Patients with louse infestation present with scalp pruritus, excoriations, cervical lymphadenopathy, and conjunctivitis. A hypersensitivity rash, or pediculid, may mimic a viral exanthem. Head lice infestation crosses all economic and social boundaries, whereas body lice infestation preferentially affects the homeless and displaced. Body lice are major vectors of diseases such as typhus, trench fever, and relapsing fever. Pubic lice infestation often is acquired as a sexually transmitted disease and may be a marker to screen for other sexually transmitted diseases. Treatment of louse infestation can be challenging. Mechanical measures, such as combing, are helpful as adjunctive measures, but most studies suggest they are not as effective as chemical agents. Resistance to chemical agents is a growing problem. Major types of resistance include knock-down resistance, glutathione-S-transferase-based resistance, and monooxygenase-based resistance. Research is needed to identify new effective treatments.