OBJECTIVES: Three-dimensional conformal radiotherapy and intensity-modulated radiotherapy permit more accurate conforming of treatment beams to the shape of target organs; other sources of geometric variations, such as patient movement, positioning uncertainties, and organ motion, can result in complications due to irradiation of normal tissues. This assessment evaluated the evidence on the Calypso® 4D Localization System (“System”). This is a real-time three-dimensional target tracking system that was developed to aid in tumor target localization during radiation therapy. It utilizes implanted wireless transponders that respond to an AC activation wave with a low-energy radio-frequency return signal that can be used to obtain real-time positional information of the target organ. METHODS: The MEDLINE® database and Cochrane Library were searched for all articles published during the period commencing January 1995 through October 2005 using subject headings and terms. A total of nine abstracts reporting limited data on the mechanism and accuracy of the System were presented at the 2004 and 2005 annual meetings of the ASTRO. Comparators included electronic portal imaging devices (EPID); CT, including standard CT and CT-on-rails; ultrasound, including B-mode Acquisition and Targeting (BAT®); and X-ray, including the CyberKnife®. RESULTS: Initial clinical results indicated eleven of 20 evaluable patients were localized and tracked with the System; compared to standard radiographic x-rays, localization and tracking by the System demonstrated a mean 3D difference of 1.5 mm (SD 0.9). Two of 11 (18%) patients exhibited significant organ motion exceeding 5 mm over an eight-minute tracking period with the excursions persisting over one minute. Preliminary data were available for five patients (193 fractions) from a second cohort which confirmed early findings. PROM also indicated patient preference for the System. CONCLUSION: 4D tracking and localization improves target organ irradiation in comparison to existing technologies because by improved detection of organ motion in real time.