The treatment of a biological system with small molecules to specifically perturb cellular functions is commonly referred to as chemical biology. Small molecules have been used commercially as drugs, herbicides, and fungicides in different systems, but in recent years they are increasingly used as tools for basic research. For instance, chemical genetics involves the discovery of small-molecule effectors of various cellular functions through screens of compound libraries. Whereas the drug discovery field has largely been driven by target-based screening approaches followed by drug optimization, chemical genetics in plant systems tends to be fueled by more general phenotype-based screens, opening the possibility to identify a wide range of small molecules that are not necessarily directly linked to the process of interest. Here we provide an overview of the current progress in chemical genetics in plants, with a focus on the discoveries regarding small molecules identified in screens designed with a basic biology perspective. We reflect on the possibilities that lay ahead and discuss some of the potential pitfalls that might be encountered upon adopting a given chemical genetics approach.