<p>Historically, systemic therapy for hormone-sensitive prostate cancer (HSPC) was predicated on androgen-deprivation therapy (ADT) alone. However, in the past decade, substantial improvements have been made by intensifying treatment based on a better understanding of the broad underlying biology of these cancers. The addition of androgen receptor pathway inhibitors (ARPIs), docetaxel and/or radiotherapy to ADT is of proven benefit in certain patient subgroups, whereas AKT inhibitors, radioligand therapies and poly ADP-ribose polymerase (PARP) inhibitors are being evaluated in patients with metastatic HSPC. The clinical states of HSPC are determined by a history of localized prostate cancer versus presentation with de novo metastatic disease, as well as the extent of disease on conventional computed tomography imaging and whole-body bone scintigraphy. However, modern nuclear imaging modalities such as prostate-specific membrane antigen PET can visualize metastases below the limit of detection of computed tomography and whole-body bone scintigraphy; this earlier and more precise detection of metastases has identified new subgroups of patients for which certain treatment approaches, such as adding docetaxel to ADT plus an ARPI, might or might not apply. In this Review, we discuss the personalized management of both non-metastatic and metastatic HSPC, including how to select patients for docetaxel, choice of ARPI and use of radiotherapy to primary and metastatic disease sites. We also discuss emerging novel therapies and important principles of toxicity mitigation for HSPC.</p>