While older external-beam radiation therapy protocols included a full dose to the whole bladder, more recently, protocols have been developed to boost the tumor bed only, using partial-bladder irradiation after a 40–45 Gy of whole-bladder radiotherapy. Due to bladder-filling rate and bladder-volume changes, there is growing evidence that image guidance is essential in order to appropriately treat bladder cancer.Compared with three-dimensional radiotherapy, the CyberKnife® system holds the potential for excellent dose distributions in bladder cancer. There is yet no example of a CyberKnife application for bladder cancer in the literature except a case report with positive outcome. Because each fraction duration is quite long (1–1.5 h), bladder surface deformations and volume changes may occur during fractions and must be taken into account. Data on prostate cancer has demonstrated the feasibility and reliability of ultrasound (US) guidance and voiding protocols in assuring consistent bladder volume for hypofractionated CyberKnife treatments.