The phosphoinositide 3-kinase (PI3K) pathway integrates multifarious environmental cues to regulate cell survival, growth, and metabolism. Hyperactivation of the PI3K pathway increases biological fitness by offering a high degree of adaptability to and resilience against diverse perturbations, thus conferring survival benefits on premalignant and transformed cells. In prostate cancer, the PI3K pathway is aberrantly activated by various genetic and epigenetic alterations and its hyperactivation is closely associated with a poor clinical outcome. In this review, we discuss the challenges encountered with clinically effective therapies targeting the PI3K pathway in prostate cancer, highlighting the clinical importance of combination therapies. In particular, we address how prostate cancer cells utilize the PI3K pathway for the development of resistance to a broad range of anticancer treatments. In addition, we describe the molecular mechanisms by which prostate cancer cells become resistant to PI3K pathway inhibitors. This review will be helpful in translating biological knowledge into therapeutic strategies for the treatment of prostate cancer and provide insight into overcoming therapeutic challenges associated with prostate cancer.