Whereas the androgen receptor (AR) protein shares similarities in the structure of its DNA- and hormone-binding domains with other members of the steroid nuclear receptor family, the molecule in its unliganded form has a seemingly unordered amino-terminal transactivation domain unique to the AR. A comprehensive understanding of the specific sub-structures and protein-protein interactions inherent to this domain in both its inactive and activated states remains un-achieved. Therefore, the malleability of this peptide region in accommodating the diverse repertoire of transcription-modulating AR cofactors creates a great challenge for those intent on generating relevant three-dimensional molecular models. The AR transactivation domain achieves this flexibility through a series of conformational steps dependent on the presence of cofactors that induce allosteric changes, and thus has evolved several conserved peptide motifs representing key protein-protein interaction surfaces. Elucidation of these signaling regions, including their involvement in inducing AR transactivation domain structural changes, is of foremost interest in understanding how the AR achieves its pivotal role in regulating the androgen signaling axis particularly during the progression of prostate cancer.