Nanomedicine is an evolving field of scientific research with unique advantages and challenges for the detection and treatment of medical diseases. Since 1995, the FDA has approved the administration of nanoparticle-based therapies. The initial generation of nanoparticles relied on an enhanced permeability and retention effect, associated with an increased penetrability of tumor related blood vessels. With increasing knowledge of biomarkers and molecular targets, active targeting of circulating tumor cells by nanoparticles provides an exciting area for application. The selective targeting of prostate cancer cells using a nanotechnology-based mechanism has the potential to optimize the delivery of therapeutic payloads directly to prostate cancer cells while minimizing systemic toxicities. The molecular targets that have been studied include prostate specific membrane antigen, gastrin-releasing peptide protein, glucose related protein, CD44, claudin, C-X-C chemokine receptor type 4 (CXCR-4), and adenosine. The clinical potential for nanoparticle-based therapies is supported by several studies that have progressed past the preclinical stage into clinical trials. In this review, we present the molecular biomarkers that have been targeted by ligands conjugated to the surface of nanoparticles for prostate cancer imaging and therapy.