Uncertainty in regional climate predictions is a critical component of understanding risks of future climate impacts. Unfortunately, while State-of-the-science Earth System Models show consistency with observations at global and hemispheric scales, they show limited skill in reproducing climate change at sub-continental and smaller scales (i.e., regional scales) despite their ability to detect and attribute climate change at global to continental scales. Significant internal/chaotic climate variability is one reason for this lack of skill. Structural uncertainty in modeling the physical climate system is an additional issue. Uncertainty in the centennial timescale trajectory of greenhouse gases and other factors impacting long-term changes is yet another component. In this talk, we will discuss components in climate models that lead to these uncertainties with a focus on basic physical processes related to both global and regional climate change.