Climate is changing around the world across a range of scales from local to global, but ecological consequences remain difficult to understand and predict. Such predictions are complicated by changes in connectivity of resources, in particular water, nutrients, and propagules, that influence the way ecological responses scale from local to regional and from regional to continental. This paper describes ecological responses at regional to continental scales associated with four key meso-scale drivers that influence the ecosystems of the continental interior: drought, warming, snowpack disappearance, and altered fire regime. These drivers will affect, for example, atmospheric smoke, dust, and reactive nitrogen concentrations; stream discharge, nitrate concentrations, and sediment loads; and the vector-borne spread of invasive species and infectious diseases. A key component of the continental network should be simulation models that describe transport vectors, particularly atmospheric, hydrologic, and human transport processes, that connect different spatial scales.