Despite the recent approval and widespread use of abiraterone acetate and enzalutamide for the treatment of castration‐resistant prostate cancer (CRPC), this disease still poses significant management challenges because of various tumor escape mechanisms, including those that allow androgen receptor (AR) signaling to remain active. These AR‐related resistance mechanisms include AR gene amplification or overexpression, constitutively active ligand‐independent AR splice variants, and gain‐of‐function mutations involving the AR ligand‐binding domain (LBD), among others. Therefore, the development of AR‐targeted therapies that function independently of the LBD represents an unmet medical need and has the potential to overcome many of these resistance mechanisms. This article discusses N‐terminal domain (NTD) inhibition as a novel concept in the field of AR‐directed therapies for prostate cancer. AR NTD‐targeting agents have the potential to overcome shortcomings of current hormonal therapies by inhibiting all forms of AR‐mediated transcriptional activity, and as a result, may affect a broader AR population including mutational and splice variant ARs. Indeed, the first clinical trial of an AR NTD inhibitor is now underway. Implications for Practice: Because of emerging resistance mechanisms that involve the ligand‐binding domain of the androgen receptor (AR), there is currently no effective treatment addressing tumor escape mechanisms related to current AR‐targeted therapies. Many patients still demonstrate limited clinical response to current hormonal agents, and castration‐resistant prostate cancer remains a lethal disease. Intense research efforts are under way to develop therapies to target resistance mechanisms, including those directed at other parts of the AR molecule. A novel small‐molecule agent, EPI‐506, represents a new pharmaceutical class, AR N‐terminal domain inhibitors, and shows preclinical promise to overcome many known resistance mechanisms related to novel hormonal therapies. This article discusses N‐terminal domain (NTD) inhibition as a novel concept in the field of androgen receptor (AR)‐directed therapies for prostate cancer. AR NTD‐targeting agents have the potential to overcome shortcomings of current hormonal therapies by inhibiting all forms of AR‐mediated transcriptional activity and, as a result, may affect a broader AR population, including mutational and splice variant ARs.