Active exchanges of water and dissolved material between the stream and groundwater in many porous sand- and gravel-bed rivers create a dynamic ecotone called the hyporheic zone. Because it lies between two heavily exploited freshwater resources - rivers and groundwater - the hyporheic zone is vulnerable to impacts coming to it through both of these habitats. This review focuses on the direct and indirect effects of human activity on ecosystem functions of the hyporheic zone. River regulation, mining, agriculture, urban, and industrial activities all have the potential to impair interstitial bacterial and invertebrate biota and disrupt the hydrological connections between the hyporheic zone and stream, groundwater, riparian, and floodplain ecosystems. Until recently, our scientific ignorance of hyporheic processes has perhaps excused the inclusion of this ecotone in river management policy. However, this no longer is the case as we become increasingly aware of the central role that the hyporheic zone plays in the maintenance of water quality and as a habitat and refuge for fauna. To fully understand the impacts of human activity on the hyporheic zone, river managers need to work with scientists to conduct long-term studies over large stretches of river. River rehabilitation and protection strategies need to prevent the degradation of linkages between the hyporheic zone and surrounding habitats while ensuring that it remains isolated from toxicants. Strategies that prevent anthropogenic restriction of exchanges may include the periodic release of environmental flows to flush silt and re-oxygenate sediments, maintenance of riparian buffers, effective land use practices, and suitable groundwater and surface water extraction policies.