Rivers are not isolated systems but continuously interact with the subsurface from upstream to downstream. In the last few decades, research on the hyporheic zone (HZ) from many perspectives has increased appreciation of the hydrological importance and ecological significance of connected river and groundwater systems. Although recent reviews, modelling and field studies have explored hydrological, biogeochemical and ecohydrological processes in the HZ at relatively small scales (bedforms to reaches), a comprehensive understanding of the factors driving the hyporheic exchange flows (HEF) at larger scales is still missing. To date, there is fragmentary information on how hydroclimatic , hydrogeologic , topographic , anthropogenic and ecological factors interact to drive hyporheic exchange flows at large scales. Further evidence is needed to link hyporheic exchange flows across scales. This review aims to conceptualize interacting factors at catchment, valley and reach scales that control spatial and temporal variations in hyporheic exchange flows. The implications of these drivers are discussed for each scale, and co-occurrences across scale are highlighted in a case of study. By using a multi-scale perspective, this review connects field observations and modelling studies to identify broad and general patterns of HEF in different catchments. This multi-scale perspective is useful to devise approaches to interpret hyporheic exchange across multiscale heterogeneities, to infer scaling relationships, and to inform watershed management decisions.