Systems and methods for transdermal drug delivery with controlled heat are provided. Such systems can comprise a heating apparatus that includes an exothermic chemical composition, typically in the form of individual heating elements. The heating apparatus can be exposed to ambient oxygen through a cover. The cover can reduce the amount of ambient oxygen capable of contacting the chemical composition compared to when the cover is not present. In some embodiments, the heating apparatus can include more than one heating element. The systems can further include a drug-containing layer that includes a drug. The drug-containing layer can have a surface area of about 50 cm.sup.2 to about 400 cm.sup.2. The systems of the present invention can be deliver ketoprofen in an amount sufficient to produce a mean blood plasma concentration of ketoprofen in a human subject of at least 45 ng/ml within four hours after initial application of the system to a skin surface.