Arthropod bites remain a major cause of patient morbidity. These bites can cause local or systemic effects that may be infectious or inflammatory in nature. Arthropods, notably insects and arachnids, are vectors of potentially serious ailments including malaria, West Nile virus, dengue, and Lyme disease. Measures to curtail the impact of insect bites are important in the worldwide public health effort to safely protect patients and prevent the spread of disease. The history of insect repellent (IR) lends insight into some of the current scientific strategies behind newer products. Active ingredients of currently available IRs include N,N-diethyl-3-methylbenzamide (DEET), botanicals, citronella, and, the newest agent, picaridin. Currently, the Environmental Protection Agency’s registered IR ingredients approved for application to the skin include DEET, picaridin, MGK-326, MGK-264, IR3535, oil of citronella, and oil of lemon eucalyptus. DEET has reigned as the most efficacious and broadly used IR for the last 6 decades, with a strong safety record and excellent protection against ticks, mosquitoes, and other arthropods. Newer agents, like picaridin and natural products such as oil of lemon eucalyptus are becoming increasingly popular because of their low toxicity, comparable efficacy, and customer approval. Various characteristics and individual product advantages may lead physicians to recommend one agent over another.