Androgen and androgen receptor (AR) signaling are crucial for the genesis ofprostate cancer (PCa),which can often develop into androgen-ligand-indepen-dent diseases that are lethal to the patients.Recent studies show that even thesehormone-refractory PCa require ligand-independent AR signaling for survival.Ascurrent chemotherapy is largely ineffective for PCa and has serious toxic side-effects,we have initiated a collaborative effort to identify and develop novel,safeand naturally occurring agents that target AR signaling from Oriental medicinalherbs for the chemoprevention and treatment of PCa.We highlight our discoveryof decursin from an Oriental formula containing Korean Angelica gigas Nakai(Dang Gui) root as a novel anti-androgen/AR agent.We have identified thefollowing mechanisms to account for the specific anti-AR actions:rapid block ofAR nuclear translocation,inhibition of binding of 5α-dihydrotestesterone to ARand increased proteasomal degradation of AR protein.Furthermore,decursinlacks the agonist activity of the“pure”anti-androgen bicalutamide and is morepotent than bicalutamide in inducing PCa apoptosis.Structure-activity analysesreveal a critical requirement of the side-chain on decursin or its structural isomerdecursinol angelate for anti-AR,cell cycle arrest and proapoptotic activities.Thiswork demonstrates the feasibility of using activity-guided fractionation in cellculture assays combined with mechanistic studies to identify novel anti-andro-gen/AR agents from complex herbal mixtures. Androgen androgen receptor (AR) signaling are crucial for the genesis of prostate cancer (PCa), which can often develop into androgen-ligand-indepen-dent diseases that are lethal to the patients. Recent studies show that even these hormone-refractory PCa require ligand -independent AR signaling for survival. Ascurrent chemotherapy is largely ineffective for PCa and has serious toxic side-effects, we have initiated a collaborative effort to identify and develop novel, safely and naturally occurring agents that target AR signaling from Oriental medicinalherbs for the chemoprevention and treatment of PCa. We highlight our discovery of decursin from an Oriental formula containing Korean Angelica gigas Nakai (Dang Gui) root as a novel anti-androgen / AR agent. We have identified thefollowing mechanisms to account for the specific anti-AR actions: rapid block ofAR nuclear translocation, inhibition of binding of 5α-dihydrotestesterone to AR and increased proteasomal degradation of AR protein. Futurerther, dec ursinlacks the agonist activity of the “pure” anti-androgen bicalutamide and is more potent than bicalutamide in inducing PCa apoptosis. Structure-activity analyzes of a critical requirement of the side-chain on decursin or its structural isomer decursinol angelate for anti-AR, cell cycle arrest and proapoptotic activities. This work demonstrates the feasibility of using activity-guided fractionation in cellculture assays combined with mechanistic studies to identify novel anti-andro-gen / AR agents from complex herbal mixtures.