As new technologies have allowed physicians to both better image and characterize malignant disease as well as deliver radiation dose with high precision and accuracy, there has been a resurgence in interest in hypofractionated or even single-fraction radiation therapy schemas. Late-reacting tissues have a low alpha/beta ratio (compared with early reacting tissues) and are therefore more sensitive to increments in fraction size. When we hypofractionate, we may lose some of the biological advantages associated with fractionation while we may simultaneously increase our risk of damaging late-responding normal tissues. The ideal 4 R's for tumor cells are exactly opposite those 4 R's ideally desired for normal tissues, and this represents the major dilemma to the practicing radiation oncologist. The long-term safety profile for modern hypofractionated radiation schemes will depend on the area and volume treated, the total dose delivered, and the level of baseline function observed before initiating radiation therapy. These issues are raised in the context of hypofractionation for central nervous system malignancies, lung cancers, pelvic malignancies, head and neck cancers, and breast cancers. If we are careful when choosing the site (and most importantly the volume), it is likely that hypofractionation may benefit our patients. However, history has taught us to be very careful when using hypofractionation to large volumes or when incorporating critical structures. With appropriate long-term follow-up, some cases of severe normal tissue toxicity can be anticipated. Hypofractionation should continue to be studied in randomized clinical trials, with a particular focus on careful follow-up.