A current challenge in cancer therapeutics is incomplete response to treatment and emergence of therapy-resistant disease. Androgen deprivation therapy (ADT), the standard treatment for advanced prostate cancer, and effectively reduces the tumour burden in most patients. Yet, residual tumour cells that withstand ADT eventually develop lethal castration-resistance. We have taken multiple different experimental approaches to understand the response of prostate cancer to androgen signalling and/or blockade at different stages of progression, including hormone sensitive and castrate-resistant prostate cancer (CRPC). To study this, we have combined novel androgen treatment strategies with contemporary prostate cancer patient-derived xenografts (PDXs). Firstly, we examined whether cancer cells that survive castration (i.e. castrate-tolerant cells) can be effectively targeted by combination treatment at the time of ADT to delay or even prevent the development of CRPC. Using single cell transcriptomics, we identified several gene expression changes induced in castrate-tolerant cells following ADT, which offer novel therapeutic targets for upfront co-treatment. Secondly, we have examined two treatment approaches for CRPC, where androgen signalling remains a key driver of disease. This involves i) effective targeting of the androgen receptor (AR) amino-terminal domain (NTD), which is distinct from the ligand-binding domain (LBD), using peptidomimetics that inhibit specific NTD:coregulator interactions essential for AR activity and CRPC growth and ii) Bipolar Androgen Therapy (BAT), which involves rapid cycling between castrate and supraphysiological androgen levels. Collectively, our data show that both NTD AR-targeting and high-dose testosterone using BAT are both effective treatments for prostate cancers, particularly for those with specific alterations in the AR, including AR variants, and DNA repair pathways. Thus, the AR continues to me a major therapeutic target in prostate cancer at all stages of disease progression.