Despite recent progress, prostate cancer (PCa) still represents a major cause of cancer-related mortality and morbidity in men. Treatment of prostate cancer is usually based on androgen deprivation therapy (ADT), which is achieved either pharmacologically or by surgical castration. However, despite initial response, the majority of patients invariably progress and eventually develop metastatic castration-resistant prostate cancer (mCRPC). Patients affected by mCRPC that do not respond to second-generation ADT (enzalutamide or abiraterone) are eventually treated with either chemotherapy or targeted therapy with limited benefit for their survival. Different clinically available prostate cancer therapies, including ADT and chemotherapy, induce cellular senescence, a state of stable arrest of the cell cycle, preventing old, damaged, or precancerous cells from dividing. Senescent cells secrete a complex cocktail of factors that drive a response called the senescence-associated secretory phenotype (SASP). This recruits T cells and NK cells of the immune system, promoting the removal of the senescent cells. Under these conditions, senescence is transient, which benefits the organism. However, when senescent cells linger, they can promote chronic inflammation resulting in tumor progression or treatment relapse. The elimination of senescent cells has therefore emerged as a promising therapeutic strategy. One possible way to target senescent cells is with so-called senolytic drugs, that kill them selectively. However, the current armamentarium of effective senolytics includes only a small number of effective compounds that are not suitable for clinical trials. Moreover, many currently available senolytics are only partially effective in prostate cancer. Therefore, there is the need to identify novel senolytic strategies that selectively target tumor cells in patients treated with therapies that enhance senescence, significantly reducing therapy resistance.