Mediterranean climate conditions are found in five large regions of the world. Rivers in these regions (med-rivers) are unique ecosystems because of their predictable winter flooding and summer drought regimes. These characteristics are key drivers of aquatic and riparian organisms, and the ecosystem functions and services they provide. Med-rivers are hotspots of biodiversity, supporting species adapted to both floods and droughts or using them for part of their life histories. At the same time, flow seasonality drives fluxes of nutrients and organic matter and, consequently, food web dynamics. Med-rivers have been affected for centuries, in some cases millennia, by multiple human activities that increasingly threaten these ecosystems worldwide. These threats include changes in land use, nutrient loads, heavy metal concentrations, salinity, water withdrawals, invasive species and, more recently, xenobiotics or emerging organic pollutants. In addition, future climate change scenarios predict increases in drought conditions and in the occurrence of extreme events, such as floods, heat waves, and wildfires. The diversity of aquatic organisms is declining more rapidly in med-rivers than in rivers anywhere else in the world and, for some taxonomic groups, Mediterranean regions have more introduced than native species. River management in med-rivers requires innovative approaches to account for both natural and human disturbances. Most research conducted in med-rivers has focused on the effects of flow seasonality and human pressures on biodiversity and ecosystem processes; however, there is a still large gap in linking basic and applied research knowledge and in engaging the general public into conservation and management practices. Little ecological and biological information is also available in several Mediterranean regions, and consequently these regions are being slow on implementing sustainable river management policies and species conservation programs.