Urbanization is an ongoing global phenomenon as more and more people are moving from rural to urban areas for better employment opportunities and a higher standard of living, leading to the growth of megacities, broadly defined as urban agglomeration with more than 10 million inhabitants. Intense activities in megacities induce high levels of air pollutants in the atmosphere that harm human health, cause regional haze and acid deposition, damage crops, influence air quality in regions far from the megacity sources, and contribute to climate change. Since the Great London Smog and the first recognized episode of Los Angeles photochemical smog seventy years ago, substantial progress has been made in improving the scientific understanding of air pollution and in developing emissions reduction technologies. However, much remains to be understood about the complex processes of atmospheric oxidation mechanisms; the formation and evolution of secondary particles, especially those containing organic species; and the influence of emerging emissions sources and changing climate on air quality and health. While air quality has substantially improved in megacities in developed regions and some in the developing regions, many still suffer from severe air pollution. Strong regional and international collaboration in data collection and assessment will be beneficial in strengthening the capacity. This article provides an overview of the sources of emissions in megacities, atmospheric physicochemical processes, air quality trends and management in a few megacities, and the impacts on health and climate. The challenges and opportunities facing megacities due to lockdown during the COVID-19 pandemic is also discussed.