Prostate cancer is the most frequently diagnosed cancer and second leading cause of cancer deaths among American men. Current therapies show early antitumor responses, but ultimately lead to treatment resistance, relapse and poorer survival in patients. Alternative RNA splicing, a cell mechanism increasing the proteome diversity by producing multiple transcripts from a single gene, has been associated with prostate cancer development/progression. Reports showed that many aberrant mRNA splice variants are upregulated in prostate cancer, promoting malignancy through enhanced proliferation, metastasis, tumor growth, anti-apoptosis, and/or treatment resistance. Here, we discuss the oncogenic properties of aberrant splicing mechanisms underlying prostate cancer pathogenesis, as well as the uses of the splicing variants as potential diagnostics and treatment targets. Finally, we discuss the pharmacologic and molecular approaches for targeting aberrant splicing mechanisms as effective therapies to correct the splicing errors and overcome the drug resistance, ultimately improving the clinical outcome of prostate cancer patients.