Despite 40 years of research on sustainability, most of the commonly used measures of sustainability such as pollution, population, consumption, biodiversity and atmospheric carbon have all worsened on a global scale. This chapter suggests we must go beyond scientific research and study problems to solve what could be termed the real-world problems of global sustainability. It discusses transdisciplinary sustainability science that is impactful and responsive to stakeholders’ needs. It seeks to understand better the interactions between natural and human systems in key challenge areas, including global climate change, food–water–energy, biodiversity and natural assets, environmental impacts on health, oceans, urbanization, sustainable consumption and production, and governance processes. It also discusses what is termed Future Earth's “knowledge action networks” designed to develop transdisciplinary, stakeholder-engaged, co-designed solutions.