Acantholytic skin disorders without a primary immunological etiology are characterized by impaired intercellular adhesion between epidermal keratinocytes. Genetic acantholytic disorders include Darier disease and Hailey-Hailey disease; the pathogenesis of Grover disease is unknown. Since these conditions are not commonly seen in clinical practice, diagnoses may be missed and there are no standardized guidelines to direct treatment. Topical steroids and retinoids are typically utilized for mild disease, and oral retinoids, particularly acitretin, have often been used for more severe disease, but efficacy is not universal. There is emerging evidence for biologics and small molecular inhibitors, including dupilumab, tumor necrosis factor-α inhibitors, apremilast, and Janus kinase inhibitors to treat refractory disease. Recent data and personal experience suggest potential efficacy of low-dose naltrexone as monotherapy or adjunctive treatment. Overactivity of the interleukin-17/23 and interleukin 4/13 axes or MAPK/ERK pathways may point to novel therapeutic strategies, including guselkumab. Direct SERCA activators may hold potential for treatment of Darier disease. This clinical review aims to equip physicians to diagnose acantholytic disorders and provide expert treatment recommendations based on emerging evidence.