An estimated 10% to 40% of children with epilepsy have treatment-resistant epilepsy. Persistent seizures have negative psychosocial, behavioral, cognitive, and financial consequences and are associated with an increased mortality rate. Accurate syndromic and etiologic diagnoses are of vital importance because they may guide medical and/or surgical decision making. Revisitation of the history to confirm the diagnosis of epilepsy and the appropriateness of medication trials to date is vital. Routine imaging should include structural magnetic resonance imaging (MRI) with an established epilepsy protocol. In the setting of a normal previous MRI, repeat imaging may be indicated and may be supplemented with other imaging modalities. The admission for prolonged inpatient video-encephalographic monitoring may lead to a revision of a pre-existing diagnosis. Laboratory evaluations should include genetic, metabolic, and infectious/inflammatory studies when indicated. In this review, we discuss the implication of seizure semiology and syndrome classification when searching for an underlying diagnosis in treatment-resistant epilepsy, and will review both basic and more advanced procedures/studies that may aid diagnosis.