It is well-established that both the initial and advanced growth of prostate cancer depends critically on androgens and thus on the activated androgen receptor (AR) -mediated signaling pathway. The unique hormone-dependent feature of prostate cancer forms the biological basis of hormone or androgen-deprivation therapy (ADT) that aims to suppress the AR signaling by androgen depletion or AR antagonists. ADT still remains the mainstay treatment option for locally advanced or metastatic prostate cancer. However, most patients upon ADT will inevitably develop therapy-resistance and progress to relapse in the form of castration-resistant disease (castration-resistant prostate cancer or CRPC) or even a more aggressive androgen-independent subtype (therapy-related neuroendocrine prostate cancer or NEPC). Recent advances show that besides AR, some ligand-independent members of nuclear receptor superfamily-designated as orphan nuclear receptors (ONRs), as their endogenous physiological ligands are either absent or not yet identified to date, also play significant roles in the growth regulation of prostate cancer via multiple AR-dependent or -independent (AR-bypass) pathways or mechanisms. In this review, we summarize the recent progress in the newly elucidated roles of ONRs in prostate cancer, with a focus on their interplay in the AR-dependent pathways (intratumoral androgen biosynthesis and suppression of AR signaling) and AR-independent pathways or cellular processes (hypoxia, oncogene- or tumor suppressor-induced senescence, apoptosis and regulation of prostate cancer stem cells). These ONRs with their newly characterized roles not only can serve as novel biomarkers but also as potential therapeutic targets for management of advanced prostate cancer. © 2020 Elsevier Ltd