Global change is not restricted to climate change, and plant species generally face multiple human-driven disturbances constraining their viability. Most importantly, interactions among these drivers frequently generate nonadditive effects that cannot be predicted based on single-factor studies. Our goal was to assess the joint effects of three global change drivers that are especially relevant in Mediterranean ecosystems, namely, fragmentation, reduced habitat quality, and climate change on Centaurea hyssopifolia, a gypsum specialist plant. We carried out a two-year study (2005-2006) in natural populations of this plant in large (>11 ha) and small (< 1.5 ha) fragments. Within each fragment, we identified areas of contrasting habitat quality as revealed by plant cover and nutrient content, and within each combination of habitat quality and fragment size we performed a rainfall manipulation experiment simulating the most likely future climate scenario for the region. Survival, growth, phenology, and reproductive success of selected plants were monitored. The three drivers profoundly affected responses of Centaurea hyssopifolia in both study years, phenology being mainly affected by changes in habitat quality and reductions in rainfall and reproductive traits being mainly affected by fragmentation. Plants in sites of poor habitat quality and plants in the dry treatment advanced most of their phenophases (flowering and dispersing earlier) and showed reduced growth rate and increased fraction of senescent leaves. Plants growing in small fragments had lower survival, lower number of viable seeds, and a reduced seed set compared to those from large fragments. We found significant synergistic interactions among drivers. For example, the interaction between fragmentation and habitat quality led to lower survival and lower relative growth in plants from small and poor-quality habitat sites. Our results highlight the importance of studies addressing simultaneously all relevant drivers of global change potentially affecting plant performance under natural conditions. In addition, the complex responses of phenology and reproductive traits of C. hyssopifolia emphasize the need for studies integrating traits from vegetative to reproductive and from the organ to the whole-plant level.