Small GTPases comprise a diverse class of signaling proteins in mammalian cells and regulate a variety of cellular processes such as cell growth, cell movement, vesicle formation, and nuclear transport. Due to their involvement in critical cellular pathways, changes in the activation state of small GTPases due to genetic mutations or alterations in gene expression can lead to human diseases. As such, the ability to control the activity of small GTPases is paramount in understanding the precise role these proteins play in human biology and in reducing their impacts on related diseases. Herein, important advances made in the development of small‐molecule‐ and protein engineering‐based strategies to control the activity of small GTPases are presented. Current approaches within each area are discussed within their historical contexts along with commentary on the importance that each technology has had on improving the ability to regulate small GTPase activity. Given this ever‐evolving toolbox for controlling small GTPase signaling, continued growth in the study of this protein class is anticipated.