Our understanding of growth factors and growth-factor receptors, signal transduction pathways, cellular survival pathways, angiogenesis, and their potential roles in prostate-cancer tumorigenesis remains a work in progress. Novel agents targeting these key mechanisms are showing promise in clinical trials. Many more agents, including those not discussed in this article, such as radio-pharmaceuticals, bisphosphonates, nutriceuticals, immunotherapy, and newer generation chemotherapy, are also showing promise as emerging treatments for prostate cancer. It is important to recognize when designing clinical trials of novel agents that traditional endpoints of disease response may not be applicable in measuring success of biologic compounds. Especially in a disease where tumor marker levels are critical for both patient and physician, additional biomarkers are necessary to better assess response. Halting drug development due to lack of response in serum PSA may lead to an unnecessary demise of an active agent.As expected, the combination of biologic agent with cytotoxic chemotherapy has a higher traditional response rate compared with biologic agent alone. The challenge of combination trials is to determine if the combination of agents will produce a higher traditional response rate compared with chemotherapy alone. For several of the agents discussed, the clinical benefit derived from a combination of biologic agent and cytotoxic chemotherapy may not justify additional drug toxicity. Efficient trial design, appropriate selection of correlative markers,and close toxicity monitoring will help improve our ability to identify promising novel agents.