Introduction: High-risk prostate cancer (HRPCa) represents a heterogeneous disease with potential risk for local and distant progression. In these patients, a multi-modal approach consisting of neoadjuvant and/or adjuvant systemic therapies has been proposed. The aim of this review is to summarize the emerging roles of neoadjuvant and adjuvant therapies in HRPCa patients. Areas covered: This review collects the most relevant phase III randomized controlled trials (RCTs) testing the effect of neoadjuvant and adjuvant systemic therapies in combination with radical prostatectomy (RP) or radiotherapy (RT) for HRPCa patients. Specifically, the review examines the benefit provided by androgen deprivation therapy (ADT), chemotherapy (CHT), and novel antiandrogen agents in this setting. A search of bibliographic databases for peer-reviewed literature was conducted. Expert commentary: Three decades of RCTs demonstrated that adjuvant ADT is fundamental in HRPCa treated with RT. Conversely, ADT and CHT did not improve the survival of HRPCa patients managed with RP. The recent introduction of novel antiandrogen agents combined with an appropriated selection of patients at risk of cancer progression, may ultimately extend the indication of neoadjuvant and adjuvant therapy in surgical- and radio-treated patients. © 2018 Informa UK Limited, trading as Taylor & Francis Group.