Hormonal therapy and chemotherapy, though active treatments for prostate cancer, are not curative for patients with metastatic disease. Targeted therapy has the potential to control, if not eradicate, cells resistant to castration and chemotherapy. Despite several years of development, however, a biologic approach with clear clinical benefits has yet to emerge from a crowded field. This review outlines the approaches being studied at Memorial Sloan-Kettering Cancer Center to optimize biologic therapy. Trials of targeted therapy are designed on the basis of a clinical states model that describes both patient clinical risks and tumor biology. Drugs that act on multiple pathways are being developed, and targets that are expressed across all phases of the disease are selected. New molecular imaging techniques permit assessments of the target before, during, and after treatment. High-throughput preclinical assays of gene expression are being developed to enhance selection of drug sequences and combinations for clinical testing.