The recent wave of enthusiasm for image guidance in radiation therapy is largely due to the advent of on-line imaging devices. The current narrow definition of image-guided radiotherapy (IGRT), in fact, essentially connotes the use of near real-time imaging during treatment delivery to reduce uncertainties in target position and should therefore be termed IGRT-D. However, a broader (and more appropriate) context of image-guidance should include: (1) detection and diagnosis, (2) delineation of target and organs at risk, (3) determining biological attributes, (4) dose distribution design, (5) dose delivery assurance and (6) deciphering treatment response through imaging i.e. the 6 D's of IGRT. Strategies to advance these areas will be discussed.