Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K–AKT–mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K–AKT–mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.