Carcinoma of the prostate is the second most common cancer in men. In spite of the most aggressive therapies, the control of metastatic prostate cancer remains an elusive objective and many patients die of secondary disease. Targeted alpha-therapy is an emerging therapeutic modality whereby a labeled protein selectively targets cancer cells and delivers a lethal payload, which can kill cancer cells in transit or preangiogenic cell clusters. Recent studies show that targeted alpha-therapy is highly cytotoxic to prostate cancer cells in vitro and can inhibit tumor growth in animal models. This review will consider alpha-emitting radionuclides and current in vitro and in vivo studies with alpha-radioconjugates, and will focus on cell-surface target antigens and targeting vectors for the treatment of prostate cancer.