Drought stress is the principal abiotic factor affecting wheat yield in arid and semi arid areas. More than 50% of the world’s wheat growing area is affected by periodic drought. Although drought may affect wheat growth during all growth stages, the reproductive and grain-filling phases are the most sensitive stages. Post-anthesis drought stress usually shortens the grain-filling period and reduces the grain-filling rate. As the synthesize storage metabolites, starchy endosperm cells also initiate a programmed cell death (PCD) that eventually affects all but the outermost cells of the endosperm. Few studies, however, have examined the effects of drought stress on PCD in wheat endosperm.This study compared PCD in developing wheat endosperm under either normal conditions or post-anthesis drought stress. Two winter wheat cultivars were used in this experiment: ‘Xindong 18’ and ‘Xindong 22’. Grain samples were collected from normal and drought stressed plants at 5 d intervals between 5 and 35 d post anthesis. During early wheat grain filling, some endosperm cells in the normal irrigation treatment exhibited deformed nuclei and a loss of membrane integrity. These symptoms were more obvious under drought stress. Moreover, drought stress increased mitochondrial dissolution. Drought stress during grain development led to changes in ABA and ETH production in grain, which increased nuclease activity in grain endosperm. Higher nuclease activity caused greater DNA fragmentation, which in turn accelerated PCD. Drought stress significantly increased the expression of four genes related to ABA (nced1, nced2,ao1, ao2). In contrast, drought significantly reduced the expression of four genes related to ETH receptors (ers1, ers2 etr1, etr2) and one gene related to PCD (dad1).The drought treatment significantly reduced the grain weight of both cultivars at maturity. Overall, the progression of PCD may reduce the transcription of genes related to storage compounds synthesis, causing declines in grain weight and quality. This suggests that altering endogenous hormone concentrations during grain filling could delay endosperm PCD, increase grain filling time, and reduce the harm of drought stress to wheat yield and quality.