Water quality issues are a major challenge that humanity is facing in the twenty-first century. Here, we review the main groups of aquatic contaminants, their effects on human health, and approaches to mitigate pollution of freshwater resources. Emphasis is placed on chemical pollution, particularly on inorganic and organic micropollutants including toxic metals and metalloids as well as a large variety of synthetic organic chemicals. Some aspects of waterborne diseases and the urgent need for improved sanitation in developing countries are also discussed. The review addresses current scientific advances to cope with the great diversity of pollutants. It is organized along the different temporal and spatial scales of global water pollution. Persistent organic pollutants (POPs) have affected water systems on a global scale for more than five decades; during that time geogenic pollutants, mining operations, and hazardous waste sites have been the most relevant sources of long-term regional and local water pollution. Agricultural chemicals and wastewater sources exert shorter-term effects on regional to local scales.