Crop improvement depends on fast and continuous scientific progress. Recent technological advances have led to remarkable breakthroughs in barley genomics and grain physiology. This chapter aims to highlight the progress in our understanding of barley grain, its functional architecture, and energy metabolism shaped by the constraints of internal hypoxia. The authors provide a current view on the relevance of programmed cell death for grain development, and mechanisms regulating sugar intake. Finally, the authors discuss the outcome of multiscale metabolic modeling studies and how they have advanced our understanding of grain physiology. This provides an insider’s view on the life of the developing barley grain and raises new questions, which remain to be answered by applying the most advanced approaches, including nuclear magnetic resonance imaging.