Early detection of prostate cancer (PCa) and advances in hormonal and chemotherapy treatments have provided great clinical benefits to patients with early stages of the disease. However, a significant proportion of patients still progress to advanced, metastatic disease, for which no effective therapies are available. Therefore, there is a critical need for new treatment modalities, ideally targeted specifically to prostate cancer cells. The recent clinical and commercial successes of monoclonal antibodies (MAbs) have made them the most rapidly expanding class of therapeutics being developed for many disease indications, including cancer. PCa is well suited for antibody-based therapy due to the size and location of recurrent and metastatic tumors, and the lack of necessity to avoid targeting the normal prostate, a nonessential organ. These properties have fostered interest in the development and clinical evaluation of therapeutic MAbs directed to both well established and newly discovered targets in PCa. MAbs directed to established targets include those approved for other solid tumors, including anti-human epidermal growth factor receptor-2 (HER2) MAb trastuzumab, anti-epidermal growth factor receptor (EGFR) MAbs cetuximab and panitumumab, and the antivascular endothelial growth factor (VEGF) MAb bevacizumab. Genomics efforts have yielded a large number of novel, clinically relevant targets in PCa with the desirable expression profiling in tumor and normal tissues, and with an implicated role in tumor growth and spread. Growing efforts are directed to the development of naked or payload-conjugated therapeutic antibodies to these targets, and a variety of MAb products are currently progressing through preclinical and various stages of clinical development. The clinical experience with some of the commercialized MAb products points out specific challenges in conducting clinical trials with targeted therapy in PCa.