Cryogen spray cooling (CSC) is an effective method to minimize epidermal damage during laser treatment of various cutaneous anomalies such as port wine stains (PWS). We examined the mechanism of heat removal by CSC from skin, and heat removal was compared for CSC and contact cooling, another precooling method for cutaneous laser therapy. Next, we examined the heat removal ability of various cryogen delivery devices using a skin phantom and an inverse heat conduction algorithm. Third, the droplet characteristics were evaluated and correlated with heat removal in the skin phantom. An ex vivo study was used to confirm the results of the phantom work. Lastly, a comparative study of the droplet characteristics used to increase heat removal was performed on in vivo human skin to verify results from previous studies. Results demonstrated that heat removal is limited in skin by its low thermal diffusivity and heat removal by evaporative cooling was negligible on skin using CSC. Next, it was determined that different cryogen delivery devices remove various amounts of heat from the skin phantom. The cause of the differing rates of heat removal was determined to be by three main factors: the initial temperature differential between the impinging droplets and substrate, velocity of the droplets, and droplet diameter. The Weber number, which is proportional to the velocity2·diameter, showed a correlation to heat removal in the skin phantom. Using an equal temperature differential, it was confirmed that an increased Weber number provided greater epidermal protection in ex vivo human skin in response to laser irradiation. Lastly, an in vivo study of human skin also demonstrated that an increased Weber number spray was better able to reduce nonspecific thermal damage, especially with darker skin types, in response to 595 nm pulsed laser irradiation. Gross purpura after irradiation was correlated to vascular damage histologically and to apoptosis, giving the clinician a visual indication of the vascular damage occurring. This study confirmed that although the low thermal diffusivity of skin is a limiting factor in heat removal, altering the droplet characteristics can increase heat removal and provide increased epidermal protection.