Objective: To review the pharmacology, pharmacokinetics, clinical trials, and safety profile of spinosad 0.9% topical lotion, a recently approved pediculicide for treatment of head lice infestation. Data Sources: English-language articles indexed in MEDLINE (1948-May 2011), Toxline, Google Scholar, International Pharmaceutical Abstracts (1970-May 2011), and Cumulative Index to Nursing and Allied Health Literature (1981-May 2011) were identified, using the search terms spinosad, head lice, and pediculosis capitis. Study Selection and Data Extraction: Available English-language articles were reviewed. Data Synthesis: In the studies that were reviewed, the percentage of patients who were lice free 14 days after the last treatment was significantly higher in the spinosad groups compared to the permethrin groups (84.6% vs 44.9% and 86.7% vs 42.9%, respectively; p < 0.001 for both studies). Additionally, the proportion of all primary and nonprimary participants determined to be lice free following only 1 treatment with the study medication was higher among patients in the spinosad groups compared with those in the permethrin groups. Application-site erythema was observed in patients in both treatment groups; however, it was more common in patients in the permethrin groups compared with those receiving spinosad (6.8% vs 3.1%, respectively; p = 0.007). No serious adverse effects were reported by patients receiving spinosad. Adherence was higher in the spinosad groups compared with the permethrin groups, although adherence overall was high in both studies. These data suggest that spinosad is a safe and effective treatment for the eradication of head lice, and the ease of administration and improved adherence with spinosad could offer an advantage over currently available treatment options. Conclusions: Because of its established efficacy, favorable safety profile, and ease of application, spinosad can be considered a convenient and effective treatment for head lice in patients aged 4 years and older.