Reactive gases and aerosols are produced by terrestrial ecosystems, processed within plant canopies, and can then be emitted into the above-canopy atmosphere. Estimates of the above-canopy fluxes are needed for quantitative earth system studies and assessments of past, present and future air quality and climate. The Model of Emissions of Gases and Aerosols from Nature (MEGAN) is described and used to quantify net terrestrial biosphere emission of isoprene into the atmosphere. MEGAN is designed for both global and regional emission modeling and has global coverage with ~1 km² spatial resolution. Field and laboratory investigations of the processes controlling isoprene emission are described and data available for model development and evaluation are summarized. The factors controlling isoprene emissions include biological, physical and chemical driving variables. MEGAN driving variables are derived from models and satellite and ground observations. Broadleaf trees, mostly in the tropics, contribute about half of the estimated global annual isoprene emission due to their relatively high emission factors and because they are often exposed to conditions that are conducive for isoprene emission. The remaining flux is primarily from shrubs which are widespread and dominate at higher latitudes. MEGAN estimates global annual isoprene emissions of ~600 Tg isoprene but the results are very sensitive to the driving variables, including temperature, solar radiation, Leaf Area Index, and plant functional type. The annual global emission estimated with MEGAN ranges from about 500 to 750 Tg isoprene depending on the driving variables that are used. Differences in estimated emissions are more than a factor of 3 for specific times and locations. It is difficult to evaluate isoprene emission estimates using the concentration distributions simulated using chemistry and transport models due to the substantial uncertainties in other model components. However, comparison with isoprene emissions estimated from satellite formaldehyde observations indicates reasonable agreement. The sensitivity of isoprene emissions to earth system changes (e.g., climate and landcover) suggests potentially large changes in future emissions. Using temperature distributions simulated by global climate models for year 2100, MEGAN estimates that isoprene emissions increase by more than a factor of two. This is considerably greater than previous estimates and additional observations are needed to evaluate and improve the methods used to predict future isoprene emissions.