A biochemical model of isoprene emission embedded within a global chemistry-climate simulation framework is applied to investigate the transient response to environmental change over the past century. In the model, the isoprene production is directly coupled to photosynthesis and depends on intercellular carbon dioxide concentration (CO2), atmospheric CO2, and canopy temperature. Sensitivity runs are performed to isolate the relative roles of individual global change drivers: CO2, physical climate, and anthropogenic land cover change (ALCC). Between 1880 and 2000, atmospheric CO2 increased by ~30% from 291 to 370 ppmv, global average surface air temperature increased by 0.7°C, and the crop cover fraction of vegetated land area more than doubled from 15 to 37%. Over the past century, isoprene emission has decreased globally by 20% from 534 to 449 Tg C/yr, while gross primary productivity has increased by 15% from 107 to 124 Pg C/yr mostly due to CO2 fertilization. In terms of individual drivers, the global isoprene source increased by 7% due to the atmospheric CO2 concentration rise (including the opposing effects of CO2 fertilization and CO2 inhibition), decreased by 22% due to ALCC, and increased by only 3% due to physical climate change. Thus, ALCC is the dominant driver of isoprene emission change. Modeled global isoprene emissions were higher in the preindustrial than in the present day. In the industrial era, isoprene emission change represents a human-induced climate forcing, analogous to land use-driven CO2 emission, not a climate feedback because temperature-driven increase was a relatively weak driver of isoprene emission change from 1880 to 2000.