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HPE is a classic example of a complex genetic trait with \u201cpseudo\u201d\u2010autosomal dominant transmission showing incomplete penetrance and variable expressivity. Clinical suspicion of HPE is typically based upon compatible craniofacial findings, the presence of developmental delay or seizures, or specific endocrinological abnormalities, and is then followed up by confirmation with brain imaging. Once a clinical diagnosis is made, a thorough genetic evaluation is necessary. This usually includes analysis of chromosomes by high\u2010resolution karyotyping, clinical assessment to rule\u2010out well recognized syndromes that are associated with HPE (e.g., Pallister\u2010Hall syndrome, Smith\u2010Lemli\u2010Opitz syndrome and others), and molecular studies of the most common HPE associated genes (e.g., <jats:italic>SHH, ZIC2<\/jats:italic> and <jats:italic>SIX3<\/jats:italic>). In this review, we provide current step\u2010by\u2010step recommendations that are medically indicated for the genetic evaluation of patients with newly diagnosed HPE. Moreover, we provide a brief review of several available methods used in molecular diagnostics of HPE and describe the advantages and limitations of both currently available and future tests as they relate to high throughput screening, cost, and the results that they may provide. 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