The main goal of our study has been to analyze the efficiency of new anticancer drugs, specifically histone deacetylase inhibitors, in tumor cells bearing a multidrug resistance phenotype. We report that the histone deacetylase inhibitors, Trichostatin A and Suberoylanilide Hydroxamic Acid (SAHA), dramatically reduce cell viability and promote apoptosis in different drug‐resistant cells, affecting in a much lesser extent to their parental drug‐sensitive counterparts. The differential effects induced by Trichostatin A and SAHA between drug‐sensitive and drug‐resistant cells are reflected on the main characteristics of the resistant phenotype. Thus, reverse transcription‐PCR and Western immunoblots confirm that both histone deacetylase inhibitors promote endogenous down‐regulation of P‐glycoprotein, which is overexpressed in the drug‐resistant cells. Transfection of drug‐sensitive cells with the P‐glycoprotein cDNA ruled out the a priori possible association between apoptosis and down‐regulation of P‐glycoprotein induced by the histone deacetylase inhibitors. The results suggest a therapeutic potential of histone deacetylase inhibitors in the treatment of cancers with acquired resistance. © 2003 Wiley‐Liss, Inc.