Whole-body exposure to high-dose radiation causes injury involving multiple organs that depends on their sensitivity to radiation. This acute radiation syndrome (ARS) is caused by a brief exposure of a major part of the body to radiation at a relatively high dose rate. ARS is characterized by an initial prodromal stage, a latent symptom-free period, a critical or manifestation phase that usually takes one of four forms (three forms): hematologic, gastrointestinal, or cardiovascular and neurological (neurovascular), depending upon the exposure dose, and a recovery phase or death. One of the most important factors in treating victims exposed to radiation is the estimation of the exposure dose. When high-dose exposure is considered, initial dose estimation must be performed in order to make strategy decisions for treatment as soon as possible. Dose estimation can be based on onset and severity of prodromal symptoms, decline in absolute lymphocyte count post exposure, and chromosomal analysis of peripheral blood lymphocytes. Moreover, dose assessment on the basis of calculation from reconstruction of the radiation event may be required. Experience of a criticality accident occurring in 1999 at Tokai-mura, Japan, showed that ARS led to multiple organ failure (MOF). This article will review ARS and discuss the possible mechanisms of MOF developing from ARS.