Hotter and drier conditions projected for the southwestern United States can have a large impact on the abundance and composition of long-lived desert plant species. We used long-term vegetation monitoring results from 39 large plots across four protected sites in the Sonoran Desert region to determine how plant species have responded to past climate variability. This cross-site analysis identified the plant species and functional types susceptible to climate change, the magnitude of their responses, and potential climate thresholds. In the relatively mesic mesquite savanna communities, perennial grasses declined with a decrease in annual precipitation, cacti increased, and there was a reversal of the Prosopis velutina expansion experienced in the 20th century in response to increasing mean annual temperature (MAT). In the more xeric Arizona Upland communities, the dominant leguminous tree, Cercidium microphyllum, declined on hillslopes, and the shrub Fouquieria splendens decreased, especially on south- and west-facing slopes in response to increasing MAT. In the most xeric shrublands, the codominant species Larrea tridentata and its hemiparasite Krameria grayi decreased with a decrease in cool season precipitation and increased aridity, respectively. This regional-scale assessment of plant species response to recent climate variability is critical for forecasting future shifts in plant community composition, structure, and productivity.