A hand-held assembly of electrically-powered devices designed to apply cold from a gaseous or liquid refrigerant (cryogen) [e.g., liquid nitrogen (LN2), nitrous oxide (N2O), carbon dioxide (CO2)] to skin, subcutaneous, and/or mucosal tissues for cryotherapy applications (e.g., surgical ablation, cosmetic, analgesic). It typically includes a single-use or reusable handpiece with disposable application tip and cryogen cartridge (e.g., N2O cartridge), whereby the cryogen is delivered through the handpiece to the tip which is applied to tissues. It can be used for dedicated applications or across clinical specialties (e.g., general surgery, dermatology, neurology, orthopaedics, gynaecology).