Water quality assessment in the region of Fez based on the physicochemical and ecotoxicological investigations is presented. The results indicate that sites located close to the most urbanized and industrialized areas are severely impaired. The major water quality problems are: low dissolved oxygen (DO), high turbidity, organic matter and ammonia contents, severe chromium and copper pollution and high acute and chronic toxicity. This results in the loss of the aquatic life which is still flourishing in the Fez River upstream from the Fez Medina. Remote sites downstream show signs of physicochemical recovery. However, even there, bioassays showed significant acute and chronic toxicity. Well water in the region of Fez has moderately poor water quality with nitrate and metal enrichments. Use of water for drinking or for agriculture from the rivers or from some wells without treatment may expose the population to health risk.