The domain of mesoscale science, where the discrete granularity of atoms and quantization of energy give way to apparently continuous and infinitely divisible matter and energy, presents a new frontier of scientific opportunity and yields new complex architectures, phenomena, and functionalities. In this article, we describe some hallmarks of mesoscale science and highlight research directions that are described in greater detail in subsequent articles in this issue of MRS Bulletin. The exciting progress of the past several years and the rich unexplored opportunities at the mesoscale offer extraordinary prospects for future advances.