Prostate cancer, like most other solid tumors, represents a heterogeneous entity consisting of a mixture of androgen-dependent and androgen-independent cells. Although proliferation of prostate tumor cells is often initially androgen-dependent, the inevitable development of androgen-insensitivity in late-stage prostate cancer renders androgen-suppressing treatments ultimately ineffective. Non-hormonal chemotherapy induces apoptosis in actively proliferating cells and is typically of little value, since prostate cancer demonstrates very slow growth kinetics. Objective response rates of < 10% and no improved survival rates have been observed in several hundred clinical studies using both experimental and approved chemotherapeutic agents. An improved understanding of the molecular mechanisms responsible for the onset of the disease, as well as the factors that control the proliferation of prostate cancer cells, have identified key changes in gene expression during cancer progression, especially from androgen-dependent to androgen-independent status. Manipulation of the genes implicated in disease progression represent an important approach for therapeutic intervention. This review summarizes recent progress that has been made with the use of antisense technology with various chemistries to modify gene expression, a strategy that seems to hold great promise for prostate cancer therapy.