Synthetic organic chemical pollutants in water and associated environmental and health issues are major challenges that people are facing in the twenty-first century. This chapter provides historical background on several man-made persistent organic chemicals and emerging "pollutants of concern" in various water resources including streams, rivers, lakes, and coastal and open ocean environments. The contaminants highlighted and discussed include pesticides, herbicides, biocides, bisphenol analogues/derivatives, phthalates, perchlorates, perfluoroalkyl substances, flame retardants, and pharmaceuticals and personal care products. The origin of these chemicals, aquatic contamination pathways, distribution, and implications for human exposure and health are discussed. Furthermore, this chapter identifies critical challenges and future research needs in removing/minimizing water contamination and exposure to these chemical contaminants to protect living resources on a global scale.