Investigations on androgen signaling alterations in the late stages of prostate cancer revealed new molecular mechanisms that may be in part responsible for failure of endocrine therapy. Both primary and metastatic lesions from prostate cancer express androgen receptor protein. Amplification of androgen receptor gene occurs in a subset of prostate cancer patients. Several point mutations of androgen receptor gene have been described; they generate receptors which are functionally activated by androgens, other steroids, and even by antihormones. The frequency of androgen receptor mutations may be high in tumor metastases. Functional activity of androgen receptor is influenced by nonsteroidal factors, such as peptide growth factors and second messengers. Thus, prostate cancer cells adapt to low androgen environment by various mechanisms utilizing androgen receptor. Therefore, new strategies for switching off the androgen receptor are needed.