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Advanced stage prostate cancer is frequently treated with androgen receptor antagonists. Improvement in patients’ survival has been achieved with the anti-androgen enzalutamide. However, there may be an increasing number of point mutations of the androgen receptor during therapy. In addition, ligand-independent activation of truncated androgen receptors may occur during anti-hormonal therapy. In prostate cancer, there is also an increased expression of coactivators and decreased expression of corepressors, thus, contributing to the disease progression. Stromal factors such as interleukins also contribute to therapy resistance. Although preclinical studies with anti-interleukin-6 antibodies opened new possibilities for treatment of prostate cancer, clinical trials have not demonstrated a survival benefit. Increased expression of glucocorticoid receptor has also been associated with advanced prostate cancer. Thus, one can consider the administration of glucocorticoid receptor antagonists in addition to anti-androgens. Stem cells have been described either after androgen treatment or androgen ablation or as a consequence of long-term use of drugs. Taken together, multiple experimental studies provided evidence on the mechanisms that limit usefulness of anti-androgens in prostate cancer.