Validation of imaging technologies is becoming increasingly important as imaging begins to take a role as a biomarker. Activities such as drug development, guided intervention, patient stratification, and therapy response assessment rely on very high measurements of sensitivity and specificity at the earliest possible time point. Imaging is capable of providing those measurements, but without validation of the results, clinical acceptance will be delayed. It must be pointed out, however, that validation is different from verification, and the role of phantoms is different for these two operations. This paper discusses the need for multiple phantoms in the role of validation in order to present optical imaging devices with the extremes of tissue states expected in real-world operation.© (2010) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.