The present study deals with attempts to deliver cyclosporin A into the deeper skin and some of the fundamental reasons why this proves so difficult. Because of different physicochemical requirements for the solution and activity of cyclosporin A and the enhancer, n-decylmethyl sulfoxide, it was hard to demonstrate increases in permeation of cyclosporin A by the enhancer in either aqueous or ethanol/water formulation. Cyclosporin A was prohibitively insoluble in aqueous media and the activity of the enhancer is diminished to ineffectiveness when it is applied in alcoholic media. However, n-decylmethyl sulfoxide action on the stratum corneum could be obtained by pretreating the skin. The effect of pretreatment with this compound on the permeation of cyclosporin A through hairless mouse skin and human skin was studied with side-by-side diffusion cells. The skin was pretreated with 10 mM n-decylmethyl sulfoxide for various durations. Cyclosporin A in an ethanol/water formulation was then placed in the donor cell, with the amount of ethanol being controlled to maintain the highest possible thermodynamic activity. Accumulations of cyclosporin A in receiver cell media, aqueous or ethanol/water, were then assessed. Permeation from two different concentrations of cyclosporin A was compared. The permeability of hairless mouse skin to cyclosporin A was increased by the pretreatment, but results with human skin were more equivocal. It appears that it will take very long pretreatments to ready human skin for topical cyclosporin A therapy.