AbstractThis article argues that scale dependence of physical and biological processes offers resistance to reductionism and has implications that support a specific kind of downward causation. I demonstrate how insights from multiscale modeling can provide a concrete mathematical interpretation of downward causation as boundary conditions for models used to represent processes at lower scales. The autonomy and role of macroscale parameters and higher-level constraints are illustrated through examples of multiscale modeling in physics, developmental biology, and systems biology. Drawing on these examples, I defend the explanatory importance of constraining relations for understanding the behavior of biological systems.