Overcoming the androgen independence of prostate tumors is considered the most critical therapeutic end point for improving survival in patients with metastatic prostate cancer. Normal epithelial and endothelial cells can undergo apoptosis when detached from the extracellular matrix (ECM), via the anoikis phenomenon. In contrast, tumor cells upon detachment from the ECM are capable of evading anoikis and metastasizing to different distant organs. Is the biological repertoire of the epithelial and endothelial cells sufficient to account for the events associated with the process of anoikis during prostate cancer metastasis? Although there is no clear answer to this question, what has become increasingly evident from the existing evidence is that molecules that induce anoikis in tumor epithelial and endothelial cells provide exciting new leads into effective therapeutic targeting as well as markers of prostate cancer progression and prediction of therapeutic resistance. This review analyzes recent findings on anoikis regulators and discusses the relevance of this unique apoptosis mode in the development of metastatic prostate cancer and identification of molecular signatures for treatment of advanced disease.