Biological small-molecule-dependent switches sense external chemical signals and transduce them into appropriate internal signals and cellular responses. Artificial molecular switches that control the function of any protein of interest using a small molecule are powerful tools for studying biology because they enable cellular responses to be controlled by inputs chosen by researcher. Furthermore, these switches can combine the generality of genetic regulation with the reversibility and temporal control afforded by small molecules. Three approaches to creating molecular switches include altering a natural switch to recognize new exogenous ligands, engineering novel allosteric responses to ligand binding, or enforcing protein localization with chemical dimerizers. Here, we discuss the development of small-molecule-dependent switches that control in a general fashion transcriptional activation, translational initiation, and protein activity posttranslationally.