Hypofractionation refers to irradiation schemes with less than 5 fractions per week and larger doses per fraction than 2 Gy. It was initiated around 1960 to ease the burden for patients who had to come to the hospital to be treated every day and to save machine time. In the treatment of breast cancer at the University of Texas M.D. Anderson Cancer Center (UTMDACC) in 1962, the acute reactions of the skin were matched in 3- and 5-day treatment. More severe late sequelae were observed in the 3-day-a-week treatment than in the 5-day treatment. In 1966 the NSD formula was published and from thereon was used to adjust the total dose based on the number of fractions. Later, the TDF and CRE formulae were used. In almost all publications, a high percentage of severe complications after hypofractionation have been reported. There is overwhelming evidence that fraction size of more than 2 Gy produces late unfavorable sequelae, and therefore, despite the inconvenience for patients and the taxing of machine time, hypofractionation should not be used, unless there is a specific rationale concerning the tumor characteristics of doing so. In that case the total dose must be corrected in order not to increase the late morbidity.