The brown recluse spider (Loxosceles reclusa) exists in significant populations mainly in the midwestern United States. Although bites can cause significant harm, envenomation is infrequent, and cases are usually clinically insignificant. Proper knowledge of the spider's habitat and lifestyle as well as the signs and symptoms of loxoscelism are needed to assess clinical cases adequately. Loxoscelism can masquerade as many serious pathologies, and vice versa, so it is important for the clinician to explore all possibilities in the differential diagnosis thoroughly. Treatments are controversial, and no conclusive test for envenomation is currently available. This review provides information to help physicians, especially in nonendemic areas, include or exclude brown recluse bite in the clinical diagnosis and provide proper care.