AbstractNear infrared imaging has presented itself as a powerful diagnostic technique with potential to serve as a minimally invasive, nonionizing method for sensitive, deep tissue diagnostic imaging. This potential is further realized with the use of nanoparticle (NP)‐based near infrared (NIR) contrast agents that are not prone to the rapid photobleaching and instability of their organic counterparts. This review discusses applications that have successfully demonstrated the utility of nanoparticles for NIR imaging, including NIR‐emitting semiconductor quantum dots (QDs), resonant gold nanoshells, and dye‐encapsulating nanoparticles. NIR QDs demonstrate superior optical performance with exceptional fluorescence brightness stability. However, the heavy metal composition and high propensity for toxicity hinder future application in clinical environments. NIR resonant gold nanoshells also exhibit brilliant signal intensities and likewise have none of the photo‐ or chemical‐instabilities characteristic of organic contrast agents. However, concerns regarding ineffectual clearance and long‐term accumulation in nontarget organs are a major issue for this technology. Finally, NIR dye‐encapsulating nanoparticles synthesized from calcium phosphate (CP) also demonstrate improved optical performances by shielding the component dye from undesirable environmental influences, thereby enhancing quantum yields, emission brightness, and fluorescent lifetime. Calcium phosphate nanoparticle (CPNP) contrast agents are neither toxic, nor have issues with long‐term sequestering, as they are readily dissolved in low pH environments and ultimately absorbed into the system. Though perhaps not as optically superior as QDs or nanoshells, these are a completely nontoxic, bioresorbable option for NP‐based NIR imaging that still effectively improves the optical performance of conventional organic agents. WIREs Nanomed Nanobiotechnol 2010 2 461–477This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vivo Nanodiagnostics and Imaging