Invasion science abounds with a diversity of hypotheses explaining aspects of the invasion process. These hypotheses can be complimentary or contradictory, and are well-supported by contrasting empirical support, making overall patterns difficult to discern across regions, systems, and taxa. We hypothesize that this empirical disparity is associated with (1) systematic differences in spatial scale (i.e. the combination of a study’s spatial extent and resolution), and (2) cross-scale interactions by which factors operating at large spatial scales establish the effects of mechanisms driving invasions at more local scales. Using a fine-resolution dataset of stream fish community covering the conterminous United States, we highlight a series of studies demonstrating how regional and spatial differences, as well as cross-scale interactions, create context-dependency in empirical support for widely tested invasion hypotheses across the landscape. Accounting for these factors may help researchers gain a broader perspective about the factors driving invasion dynamics at large spatial extents.