Many scientific theories and discoveries involve reasoning about extreme scales, removed from human experience, such as time in geology and size in nanoscience. Thus, understanding scale is central to science, technology, engineering, and mathematics. Unfortunately, novices have trouble understanding and comparing sizes of unfamiliar large and small magnitudes. Relational reasoning is a promising tool to bridge the gap between direct experience and phenomena at extreme scales. However, instruction does not always improve understanding, and analogies can fail to bring about conceptual change, and even mislead students. Here, we review how people reason about phenomena across scales, in three sections: (a) we develop a framework for how relational reasoning supports understanding extreme scales; (b) we identify cognitive barriers to aligning human and extreme scales; and (c) we outline a theory-based approach to teaching scale information using relational reasoning, present two successful learning activities, and consider the role of a unified scale instruction across STEM education.