Intrinsic and acquired resistance to chemotherapeutic agents represents the major clinical obstacle in the control of most tumours. In vitro studies have established that multiple mechanisms, including changes in drug uptake and efflux and in detoxifying enzymes, are responsible for drug resistance. Among the latter, glutathione S transferases (GST) have been recognized to play a relevant role. In the present study we have evaluated GST pi immunohistochemically as well as enzymatically in benign and malignant primary and metastatic lesions of the melanocyte lineage. A parallel analysis of the multiple drug resistance (MDRI) gene product was performed in a representative number of specimens. Results of this study demonstrate that while GST pi is constitutively expressed by the melanocyte lineage, independently from the transformed stage, MDRI p-glycoprotein is detected with a significantly lower frequency. These findings clearly indicate that GST pi represents the major detoxifying metabolic pathway of the melanocyte lineage and may be responsible for the high degree of inherent resistance of malignant melanoma to available cytostatic treatments.