Anthropogenic increases of greenhouse gases warm the troposphere but have a cooling effect in the middle and upper atmosphere. The steady increase of CO2 is the dominant cause of upper atmosphere trends; other drivers are long-term changes of radiatively active trace gases such as CH4, O3, and H2O, secular change of solar and geomagnetic activity, and evolution of the Earth's magnetic field. Observational and model studies have confirmed that in the past several decades, global cooling has occurred in the mesosphere and thermosphere; the cooling and contraction of the upper atmosphere has lowered the ionosphere and increased electron density in the E and F1 regions. Trends of other parameters, including the F2 region, mesospheric clouds, and mesopause wave activity, have been more controversial. Modeling investigations have demonstrated that both greenhouse gas forcing and secular change of the Earth's magnetic field can cause regional, diurnal, and seasonal variability of trends in F2 region density and height, which may contribute to discrepancies regarding ionospheric trends. Recent studies also may have reconciled discrepancies between space-based and ground-based observations of mesospheric clouds: both types of observations do not find statistically significant trends in the ∼54°N–∼64°N latitude region, but space-based observations indicate that clouds may be increasing in frequency at higher latitude. Limited observational studies have suggested possible trends in wave activity. Changes in atmospheric dynamics, both as a consequence of global change in the lower and middle atmosphere and as a possible driver of trends in the upper atmosphere, is one of the critical open questions regarding trends in the upper atmosphere and ionosphere.