Water availability is a major limitation for crop productivity. Over 34 % of crop and livestock production loss is traced to drought, costing the sector $37 billion overall. Our group applies chemical biology to understand drought tolerance and to develop biotechnological tools to fight climate change. In an attempt to make discoveries with an impact in agriculture, we study different plant species including maize, rice and tomato but also model plants like Arabidopsis and the C4-monocot model Setaria viridis. During the last years we have followed a drug discovery approach to design, screen, synthesize and evaluate small molecules able to activate drought resistance in crops. Structure-guided ligand design is a powerful approach, no frequently used in plant biology, which has allowed us to develop potent ABA-receptor agonists. We are collaborating with the private sector to further improve these compounds. In the next years, we will extend our research to different targets in order to develop novel chemical probes with biotechnological interest.