Delusional infestation (DI) is a disorder in which patients express a firm, unwavering belief that they are infested with some type of organism but otherwise have a typical grasp on reality with relatively normal cognitive functioning. Although classified as a somatic delusional disorder, DI requires special consideration due to its complicated clinical presentation, requiring attention to several possible explanations for the symptoms the patients describe. The purpose of the current review is to first summarize the clinical background and features of the diagnosis then explore treatment options. DI is a rare disorder though has reported cases dating back to the 19th century and spanning across the globe. Patients often experience the disorder as secondary to a medical condition, including substance use/withdrawal. However, there have also been many reported cases of primary DI, occurring in the absence of any other psychiatric or medical disorder.Clinically, DI is a diagnosis of exclusion, where the physician must rule out other medical conditions, including genuine dermatological disorders or infestations, or contributions from medications or substances. Patients with the disorder more commonly present to nonpsychiatric healthcare providers, making it essential for all clinicians to be able to identify the disease. Treatment can include either first or second generation antipsychotics, but it is important to proceed tactfully in discourse with the patient, being careful to address patients in a straightforward manner without reinforcing or questioning the delusion and focusing conversation on what can be done for the symptoms. Future research can continue to evaluate pathophysiology underlying primary DI, which historically has been an under-studied topic.