Lipid-soluble psychotropics are often used to treat skin diseases with psychosomatic indications. Although these drugs are known to exert their effects through the central nervous system, relatively little is known about their mechanism of action in skin. In this communication, several lipid-soluble psychotropic drugs have been examined for their ability to inhibit protein kinase C (PKC)-catalyzed phosphorylation of exogenous substrates and endogenous skin proteins. Phosphorylation of three discrete skin protein substrates at 64, 42 and 28 kDa and a group crowded together at 15-18 kDa was prevented by the antidepressants/antipsychotics. Inhibition was more pronounced in a phospholipid (PL) dependent system, but both drug-PL and drug-PKC interactions seem to be important in the mechanism of action of these drugs. In addition to the tricyclic nucleus, the propanamine side chain or its N-methyl form may influence the interaction of these drugs with PKC and its substrate(s). Chlorpromazine, imipramine, fluoxetine, doxepin, amitriptyline and hydroxyzine used in the practice of dermatology may exert their therapeutic effects by modulating skin PKC activity.