Relationships between the in vitro permeation rates of select narcotic analgesics through human skin and their physicochemical properties were investigated by following the permeation kinetics of six representative compounds in small diffusion cells. The relative permeability coefficients of three phenylpiperidine analogues, meperidine, fentanyl, and sufentanil, all measured on a single piece of skin, were 3.7 × 10−3, 5.6 × 10−3, and 1.2 × 10−2 cm/hr, respectively. Using membranes from the same skin section, the permeability coefficients of three opioid alkaloids, morphine, codeine, and hydromorphone, were considerably lower, at 9.3 × 10−6, 4.9 × 10−5, and 1.4 × 10−5 cm/hr, respectively. The high permeability coefficients of the former compounds are due to their highly lipophilic nature as reflected in high octanol/water partition coefficients and low solubility parameters. Generally, the permeability coefficients of the narcotics increase as the lipophilicity increases. When viewed in literature perspective, the data suggest that aqueous tissue control of transport is approached in the case of the phenylpiperidine analogues, all of which have Koctanol/water values greater than 40. Permeability coefficients of fentanyl and sufentanil were also determined as a function of pH over the pH range 7.4 to 9.4, in this instance with membranes prepared from additional samples of skin. The permeability coefficients of each drug varied less than threefold over the pH range, a behavior consistent with the highly hydrophobic natures of the compounds. The low permeability coefficients of morphine, codeine, and hydromorphone coupled with their low potencies make these drugs poor transdermal candidates. It appears that fentanyl and sufentanil can be successfully transdermally delivered.