Active transportation is defined as self-propelled, human-powered transportation modes, such as walking and bicycling. In this article, we review the evidence that reliance on gasoline-powered transportation is contributing to global climate change, air pollution, and physical inactivity and that this is harmful to human health. Global climate change poses a major threat to human health and in the future could offset the health gains achieved over the last 100 yr. Based on hundreds of scientific studies, there is strong evidence that human-caused greenhouse gas emissions are contributing to global climate change. Climate change is associated with increased severity of storms, flooding, rising sea levels, hotter climates, and drought, all leading to increased morbidity and mortality. Along with increases in atmospheric CO2, other pollutants such as nitrogen dioxide, ozone, and particulate matter (e.g., PM2.5) are released by combustion engines and industry, which can lead to pulmonary and cardiovascular diseases. Also, as car ownership and vehicle miles traveled have increased, the shift toward motorized transport has contributed to physical inactivity. Each of these global challenges has resulted in, or is projected to result in, millions of premature deaths each year. One of the ways that nations can mitigate the health consequences of climate change, air pollution, and chronic diseases is through the use of active transportation. Research indicates that populations that rely heavily on active transportation enjoy better health and increased longevity. In summary, active transportation has tremendous potential to simultaneously address three global public health challenges of the 21st century.