Recent research has identified a link between the global mean signal of resting‐state functional MRI (fMRI) and macro‐scale cerebrospinal fluid movement, indicating the potential link between this resting‐state dynamic and brain waste clearance. Consistent with this notion, the strength of this coupling has been associated with multiple neurodegenerative disease pathologies, especially the build‐up of toxic proteins. This article aimed to review the latest advancements in this research area, emphasizing studies on spontaneous global brain activity that is tightly linked to the global mean resting‐state fMRI signal, and aimed to discuss potential mechanisms through which this activity and associated physiological modulations might affect brain waste clearance. The available evidence supports the presence of a highly organized global brain activity that is linked to arousal and memory systems. This global brain dynamic, along with its associated physiological modulations, has the potential to influence brain waste clearance through multiple pathways through multiple pathways.Level of Evidence2Technical EfficacyStage 3