Transboundary pollution in the Tijuana River Valley has persisted for nearly a century, and previous infrastructure developments to control contamination in the river have consistently failed to solve the problem. Under the United States-Mexico-Canada Agreement of 2020, the U.S. Environmental Protection Agency has been named as the lead U.S. agency for new projects in the Tijuana River Valley to mitigate contaminated transboundary flows from Mexico. The agreement also includes $300 million in funds dedicated to new these new projects. The new project proposals put forth by the EPA, of which there are nine, are designed to either divert and treat main river flow, treat sewage, or control trash and sediment. Diverting main river flow in the Tijuana River will reduce the risk of flooding during wet weather as well as mitigate pollution from urban and industrial runoff. Of the EPA projects proposed, diverting main channel flow in the Tijuana River to the Rodriguez Reservoir for indirect potable reuse has the potential to not only reduce untreated wastewater and runoff from entering the estuary and ocean, but also provide additional drinking water supply to Tijuana. Untreated sewage, the most prominent blight in the Tijuana River and its tributaries, poses a risk to human health in the form of pathogens and gastrointestinal illnesses, as well as risks to ecosystem health. Upgrading the San Antonio de los Buenos Treatment Plant in Tijuana will offer the greatest reduction in sewage contamination along San Diego’s coastal waters. The dangers of plastic pollution, including microplastics, and sediment contaminated by urban and industrial pollution can be mitigated by trash booms and sediment basins, though increased efforts at source control for both trash and sediment will be essential. As the EPA continues its evaluation of the nine proposed projects, a holistic, regional view of the causes and consequences of pollution in the Tijuana River Valley should guide the decision-making process.