Climate change, alteration of atmospheric composition, land abandonment in some areas and land use intensification in others, wildfires and biological invasions threaten forests, shrublands and pastures all over the world. However, the impacts of the combinations between global change factors are not well understood despite its pressing importance. Here we posit that reviewing global change factors combination in an exemplary region can highlight the necessary aspects in order to better understand the challenges we face, warning about the consequences, and showing the challenges ahead of us. The forests, shrublands and pastures of the Mediterranean Basin are an ideal scenario for the study of these combinations due to its spatial and temporal heterogeneity, increasing and diverse human population and the historical legacy of land use transformations. The combination of multiple global change factors in the Basin shows different ecological effects. Some interactions alter the effects of a single factor, as drought enhances or decreases the effects of atmospheric components on plant ecophysiology. Several interactions generate new impacts: drought and land use changes, among others, alter water resources and lead to land degradation, vegetation regeneration decline, and expansion of forest diseases. Finally, different factors can occur alone or simultaneously leading to further increases in the risk of fires and biological invasions. The transitional nature of the Basin between temperate and arid climates involves a risk of irreversible ecosystem change towards more arid states. However, combinations between factors lead to unpredictable ecosystem alteration that goes beyond the particular consequences of drought. Complex global change scenarios should be studied in the Mediterranean and other regions of the world, including interregional studies. Here we show the inherent uncertainty of this complexity, which should be included in any management strategy.The present review is an outcome of the research project MONTESConsolider (CSD2008-00040), funded by the Spanish Ministry of Economy and Competitiveness.Peer Reviewe