The androgen receptor (AR) is a major driver of prostate cancer and the primary therapeutic target. Recent approvals of potent second-generation AR-targeted therapies – including the AR antagonist Enzalutamide and androgen synthesis inhibitor Abiraterone – have improved outcomes for men with advanced prostate cancer, but are never curative. All AR-targeted therapies in clinical use aim to disrupt AR’s ligand-binding activity, but we believe that this strategy is approaching a ceiling of benefit for patients. In this presentation, I will describe our group’s efforts to develop novel therapeutic approaches to target the AR, including strategies aimed at: i) inhibiting the AR amino-terminal domain; and ii) “reprogramming” AR activity such that it promotes a differentiative, rather than oncogenic, transcriptional program.